Note: Descriptions are shown in the official language in which they were submitted.
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FACTOR Xa INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. 119(e) to U.S.
provisional
application serial No. 60/883,734, filed on January 5, 2007, which is
incorporated herein by
reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
This invention is directed to substituted triazole compounds which act as
inhibitors
of Factor Xa. This invention is also directed to pharmaceutical compositions
containing the
substituted triazole compounds and methods of using the compounds or
compositions to
treat a condition characterized by undesired thrombosis. The invention is also
directed to
methods of making the compounds described herein.
State of the Art
Hemostasis, the control of bleeding, occurs by surgical means, or by the
physiological properties of vasoconstriction and coagulation. This invention
is particularly
concerned with blood coagulation and ways in which it assists in maintaining
the integrity
of mammalian circulation after injury, inflammation, disease, congenital
defect, dysfunction
or other disruption. Although platelets and blood coagulation are both
involved in restoring
hemostasis and in thrombotic diseases, certain components of the coagulation
cascade are
primarily responsible for the amplification and acceleration of the processes
involved in
platelet aggregation and fibrin deposition which are major events in
thrombosis and
hemostasis.
Clot formation involves the conversion of fibrinogen to fibrin which
polymerizes
into a network to restore hemostasis after injury. A similar process results
in occluded
blood vessels in thrombotic diseases. The conversion of fibrinogen to fibrin
is catalyzed by
thrombin, the end product of a series of reactions in the blood coagulation
cascade.
Thrombin is also a key player in activating platelets, thereby contributing to
thrombosis
under conditions of both arterial and venous blood flow. For these reasons, it
has been
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postulated that efficient regulation of thrombin can lead to efficient
regulation of
thrombosis. Several classes of currently used anticoagulants directly or
indirectly affect
thrombin (e.g. unfractionated heparins, low-molecular weight heparins, heparin-
like
compounds, pentasaccharide and warfarin). Direct or indirect inhibition of
thrombin
activity has also been the focus of a variety of anticoagulants in clinical
development
(reviewed by Eriksson and Quinlan, Drugs 11: 1411-1429, 2006).
Prothrombin, the precursor for thrombin, is converted to the active enzyme by
factor
Xa. Localized activation of tissue factor/factor VIIa mediated factor Xa
generation is
amplified by the factor IXa/factor VIIIa complex and leads to prothrombinase
assembly on
activated platelets. Factor Xa, as a part of the prothrombinase complex, is
the sole enzyme
responsible for sustained thrombin formation in the vasculature. Factor Xa is
a serine
protease, the activated form of its precursor Factor X, and a member of the
calcium ion
binding, gamma carboxyglutamic acid (GLA)-containing, vitamin K dependent,
blood
coagulation factors. Unlike thrombin, which acts on a variety of protein
substrates
including fibrinogen and the PAR receptors (Protease activated receptors,
Coughlin, J
Thrombosis Haemostasis 3: 1800-1814, 2005), factor Xa appears to have a single
physiologic substrate, namely prothrombin. Since one molecule of factor Xa may
be able to
generate greater than 1000 molecules of thrombin (Mann, et al., J. Thrombosis.
Haemostasis 1: 1504-1514, 2003), direct inhibition of factor Xa as a way of
indirectly
inhibiting the formation of thrombin is considered an efficient anticoagulant
strategy. This
assertion is based on the key role of prothrombinase in thrombin synthesis and
on the fact
that inhibition of prothrombinase will have a pronounced effect on the overall
platelet
aggregation and clotting pathways. Activated proteases such as factor VIIa,
factor IXa or
factor Xa have poor proteolytic activity on their own. However, their assembly
into
cofactor-dependent, membrane-bound complexes significantly enhances their
catalytic
efficiencies. This effect is most dramatic for factor Xa, where the efficiency
is increased by
a factor of 105 (Mann, et al., Blood 76(1):1-16, 1990). Due to the higher
concentration of
the zymogens present in blood (1.4 micromolar prothrombin versus 150 nanomolar
factor
X) and the kinetics of activation, a smaller amount of factor Xa than thrombin
needs to be
inhibited to achieve an anticoagulant effect. Indirect proof of the hypothesis
of superiority
of factor Xa as a therapeutic target compared to thrombin can also be found in
clinical trials
for the prevention of deep vein thrombosis. Fondaparinux, an antithrombin III
dependent
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factor Xa inhibitor, was proven to be superior to enoxaparin (a low molecular
weight
heparin that inhibits both thrombin and factor Xa) in four trials of
orthopedic surgery
(Turpie, et al., Archives Internal Medicine 162(16): 1833-1840, 2002).
Therefore, it has
been suggested that compounds which selectively inhibit factor Xa may be
useful as in vitro
diagnostic agents, or for therapeutic administration in certain thrombotic
disorders, see e.g.,
WO 94/13693.
Several Factor Xa inhibitors have been reported as polypeptides derived from
hematophagous organisms, as well as compounds which are not large polypeptide-
type
inhibitors. Additional Factor Xa inhibitors include small molecule organic
compounds,
such as nitrogen containing heterocyclic compounds which have amidino
substituent
groups, wherein two functional groups of the compounds can bind to Factor Xa
at two of its
active sites. For example, WO 98/28269 describes pyrazole compounds having a
terminal
C(=NH)-NH2 group; WO 97/21437 describes benzimidazole compounds substituted by
a
basic radical which are connected to a naphthyl group via a straight or
branched chain
alkylene, -C(=O) or -S(=O)2 bridging group; WO 99/10316 describes compounds
having a
4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-alkylamidino-piperidine
group
connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge;
and EP
798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group
connected to an amidinonaphthyl group via a substituted or unsubstituted
sulfonamide or
carboxamide bridging group. Additional reported Factor Xa inhibitors include
those having
a structure comprising a phenyl-amidino, phenyl and halo-phenyl connected via
amide
linkages (U.S. Patent No. 6,844,367 Bl). Other Factor Xa inhibitors by the
same group
have replaced the halo-phenyl with a halo-pyridyl (see U.S. Patent Nos.
6,376,515 B2 and
6,835,739 B2).
There exists a need for effective therapeutic agents for the regulation of
hemostasis,
and for the prevention and treatment of thrombus formation and other
pathological
processes in the vasculature induced by thrombin such as restenosis and
inflammation. In
particular, there continues to be a need for compounds which selectively
inhibit factor Xa or
its precursors. Compounds that have different combinations of bridging groups
and
functional groups than compounds previously discovered are needed,
particularly
compounds which selectively or preferentially bind to Factor Xa. Compounds
with a higher
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degree of binding to Factor Xa than to thrombin are desired, especially those
compounds
having good bioavailability and/or solubility.
BRIEF SUMMARY OF THE INVENTION
The present invention provides in one embodiment, a compound having Formula
(I)
or a pharmaceutically acceptable salt, ester, or prodrug thereof:
R'
s N H
R N -~N ~
p S \
R2 O
(R4)n
v/ (I)
wherein
Ri is halogen;
R2 is hydrogen or halogen;
R3 is selected from the group consisting of -NO2, -NRsaRsb -L-NRsaRSb
-NHC(O)NRsaRsb, -NHC(O)Rs , -NHC(O)Y, Ci_6 alkyl, -CO2H, -C(O)NR5aR5b,
-C(O)NRSaY, -C(O)NH-L-Y, -OH, C1_6 alkoxy, -O-L-NR5aR5b,
-O-L-O-C(O)NRsaRsb, -Y, -O-Y, -O-L-Y, -O-L-Y-L-Y, and -S(O)pRs , wherein
said Ci_6 alkyl and Ci_6 alkoxy are optionally substituted with one to three
substituents selected from R6;
R4 is independently selected from the group consisting of halogen, -OH, -O-L-
Y,
-O-L-NRsaRsb, and C1_6 alkoxy optionally substituted with one to three
substituents selected from R6;
L is Ci-C4 alkylene;
Y is aryl, heteroaryl, or heterocyclic ring, wherein said aryl and heteroaryl
are
optionally substituted with one to three R6 and said heterocyclic ring is
optionally substituted with oxo and optionally with one to three R6 or Rg;
R 5a and Rsb are independently hydrogen or Ci_g alkyl optionally substituted
with one
to three R6, or R5a and Rsb together with the nitrogen atom to which they are
both
attached to form a 5 to 7 membered heterocyclic ring optionally having one
additional ring heteroatom selected from N, NR6, 0, and S(O)p and where said
ring is optionally substituted with one to three substituents selected from
R6;
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R5a is Ci_g alkyl optionally substituted with one to three R6;
R6 is independently selected from the group consisting of halogen, -OH, -R', -
OR',
oxo, -SR7, -S(O)R7, -S(O)zR', -SOzNHz, -C(O)NH2, -C(O)R7, -C(NH)R7,
-NHC(O)R7, -NHC(NH)R', -NHC(O)NH2, -CO2H, -NH2, -NHR7, -N(R7)2;
R' is independently C1_6 alkyl;
R8 is -L-heteroaryl optionally substituted with one to three substituents
selected from
R6;
n is 0, 1, or 2;
p is 0, 1, or 2; and
dashed lines --- are independently single or double bonds;
provided that R3 is not
~\
~-NN-R1 1
where Rii is hydrogen or alkyl.
The present invention further provides chemical intermediates, pharmaceutical
compositions and methods for preventing or treating a condition in a mammal
characterized
by undesired thrombosis comprising the step of administering to said mammal a
therapeutically effective amount of a compound of the present invention. Such
conditions
include but are not limited to acute coronary syndrome, myocardial infarction,
unstable
angina, refractory angina, occlusive coronary thrombus occurring post-
thrombolytic therapy
or post-coronary angioplasty, a thrombotically mediated cerebrovascular
syndrome, embolic
stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep
venous
thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular
coagulation,
thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic
disease
associated with heparin-induced thrombocytopenia, thrombotic complications
associated
with extracorporeal circulation, thrombotic complications associated with
instrumentation
such as cardiac or other intravascular catheterization, intra-aortic balloon
pump, coronary
stent or cardiac valve, conditions requiring the fitting of prosthetic
devices, and the like.
The present invention further provides methods for inhibiting the coagulation
of a
blood sample comprising contacting said sample with a compound of the present
invention.
These and other embodiments of the present invention are further described in
the
text that follows.
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DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The term "alkyl", by itself or as part of another substituent, means, unless
otherwise
stated, a straight or branched chain hydrocarbon radical, having the number of
carbon atoms
designated (i.e. Ci-g means one to eight carbons). Examples of alkyl groups
include methyl,
ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-
hexyl, n-heptyl,
n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group
is one having
one or more, preferably 1 to 3, double bonds. Similarly, the term "alkynyl"
refers to an
unsaturated alkyl group having one or more, preferably 1 to 3, triple bonds.
Examples of
such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-
isopentenyl, 2-
(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-
propynyl, 3-butynyl,
and the higher homologs and isomers.
The term "cycloalkyl" refers to hydrocarbon rings having the indicated number
of
ring atoms (e.g., C3_6 cycloalkyl) and being fully saturated between ring
vertices. The term
"cycloalkenyl" refers to a cycloalkyl group that has at least one point of
alkenyl
unsaturation between the ring vertices. The term "cycloalkynyl" refers to a
cycloalkyl
group that has at least one point of alkynyl unsaturation between the ring
vertices. When
"cycloalkyl" is used in combination with "alkyl", as in C3_5 cycloalkyl-alkyl,
the cycloalkyl
portion is meant to have the stated number of carbon atoms (e.g., from three
to five carbon
atoms), while the alkyl portion is an alkylene moiety having from one to three
carbon atoms
(e.g., -CH2-, -CH2CH2- or -CH2CH2CH2-).
The term "alkylene" by itself or as part of another substituent means a
divalent
radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically,
an alkyl
(or alkylene) group will have from 1 to 24 carbon atoms, with those groups
having 10 or
fewer carbon atoms being preferred in the present invention. A "lower alkyl"
or "lower
alkylene" is a shorter chain alkyl or alkylene group, generally having four or
fewer carbon
atoms.
The terms "alkoxy," "alkylamino," and "alkylthio" (or "thioalkoxy") are used
in
their conventional sense, and refer to those alkyl groups attached to the
remainder of the
molecule via an oxygen atom (-O-alkyl), an amino group, or a sulfur atom (-S-
alkyl),
respectively. Additionally, for dialkylamino groups (typically provided as -
NRaRb or a
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variant thereof, where Ra and Rb are independently alkyl or substituted
alkyl), the alkyl
portions can be the same or different and can also be combined to form a 3-7
membered
ring with the nitrogen atom to which each is attached. Accordingly, a group
represented as
-NRaRb is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl
and the like.
The terms "halo" or "halogen," by themselves or as part of another
substituent,
mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
Additionally,
terms such as "haloalkyl," are meant to include monohaloalkyl and
polyhaloalkyl up to the
maximum number of halogens permitted. For example, the term "Ci-4 haloalkyl"
is mean to
include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,
and the like.
The term "hydroxy" or "hydroxyl" refers to the group -OH.
The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic,
hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single
ring or
multiple rings (up to three rings) which are fused together or linked
covalently. The term
"heteroaryl" refers to aryl groups (or rings) that contain from one to five
heteroatoms
selected from N, 0, and S, wherein the nitrogen and sulfur atoms are
optionally oxidized,
and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be
attached to
the remainder of the molecule through a heteroatom or through a carbon atom
and can
contain 5 to 10 carbon atoms. In embodiments where multiple rings are fused or
linked
covalently, condensed (e.g., naphthyl or anthryl), not all rings need be
aromatic (e.g., 2-
benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that
the point
of attachment is at an aromatic ring. Non-limiting examples of aryl groups
include phenyl,
naphthyl and biphenyl, while non-limiting examples of heteroaryl groups
include 1-
pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-
imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-
isoxazolyl, 2-
thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-
pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-
benzimidazolyl,
benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-
quinoxalinyl, 3-
quinolyl, and 6-quinolyl. If not specifically stated, substituents for each of
the above noted
aryl and heteroaryl ring systems are selected from the group of acceptable
substituents
described below.
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For brevity, the term "aryl" when used in combination with other terms (e.g.,
aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as
defined above.
Thus, the term "arylalkyl" is meant to include those radicals in which an aryl
or heteroaryl
group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl
and the like).
The term "heterocycle" or "heterocyclyl" or "heterocyclic" refers to a
saturated or
unsaturated non-aromatic cyclic group containing at least one sulfur, nitrogen
or oxygen
heteroatom. Each heterocycle can be attached at any available ring carbon or
heteroatom.
Each heterocycle may have one or more rings. When multiple rings are present,
they can be
fused together or linked covalently, and one or more the rings can be
cycloalkyl, aryl or
heteroaryl provided that the point of attachment is through the heterocyclic
ring. Each
heterocycle must contain at least one heteroatom (typically 1 to 5
heteroatoms) selected
from nitrogen, oxygen or sulfur. Preferably, these groups contain 1-10 carbon
atoms, 0-5
nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms, wherein the sulfur
atoms are
optionally oxidized and the nitrogen atoms are optionally quatemized. More
preferably,
these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen
atoms.
Non-limiting examples of heterocycle and heteroaryl groups include pyridine,
pyridimidine, pyrazine, morpholin-3-one, piperazine-2-one, pyridine-2-one,
piperidine,
morpholine, piperazine, isoxazole, isothiazole, pyrazole, imidazole, oxazole,
thiazole,
isoxazoline, pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-
oxadiazole,
1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyrazol-5-one,
pyrrolidine-2,5-dione,
imidazolidine-2,4-dione, pyrrolidine, pyrrole, furan, thiophene, and the like.
The term "heterocycloalkyl" refers to the group alkylene-heterocycle, wherein
both
heterocycle and alkylene are as defined above.
The above terms (e.g., "alkyl," "alkoxy," "aryl" and "heteroaryl"), in some
embodiments, will include both substituted and unsubstituted forms of the
indicated radical.
Preferred substituents for each type of radical are provided below. For
brevity, the terms
aryl and heteroaryl will refer to substituted or unsubstituted versions as
provided below.
Substituents for the "alkyl," "alkoxy," aryl and heteroaryl, etc. groups are
varied and
are generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN,
-NOz,
-COzR', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)zR', -NR'-,
C(O)NR"R"', -NH-C(NHz)=NH, -NR'C(NHz)=NH, -NH-C(NHz)=NR', -S(O)R', -S(O)2R',
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-S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-
C4)alkyl, in a
number ranging from zero to the total number of open valences on the aromatic
ring system;
and where R', R" and R"' are independently selected from hydrogen, Ci_galkyl,
C3_6cycloalkyl, C2_galkenyl, C2_galkynyl, unsubstituted aryl and heteroaryl,
(unsubstituted
aryl)-Ci-4alkyl, and unsubstituted aryloxy-Ci-4alkyl. In some embodiments, the
nitrogen
atoms in the substituents are optionally quaternized. Other suitable
substituents include
each of the above aryl substituents attached to a ring atom by an alkylene
tether of from 1-4
carbon atoms.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q U-,
wherein T and
U are independently -NH-, -0-, -CH2- or a single bond, and q is an integer of
from 0 to 2.
Alternatively, two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may
optionally be replaced with a substituent of the formula -A-(CH2)r B-, wherein
A and B are
independently -CH2-, -0-, -NH-, -S-, -S(O)-5 -S(O)2-, -S(O)2NR'- or a single
bond, and r is
an integer of from 1 to 3. One of the single bonds of the new ring so formed
may optionally
be replaced with a double bond. Alternatively, two of the substituents on
adjacent atoms of
the aryl or heteroaryl ring may optionally be replaced with a substituent of
the formula
-(CH2)s-X-(CH2)t-, where s and t are independently integers of from 0 to 3,
and X is -0-,
-NR'-, -S-, -S(O)-5 -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -
S(O)2NR'- is
selected from hydrogen or unsubstituted Ci-6alkyl.
As used herein, the term "heteroatom" is meant to include oxygen (0), nitrogen
(N),
sulfur (S) and silicon (Si).
It is understood that the above definitions are not intended to include
impermissible
substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such
impermissible
substitution patterns are well known to the skilled artisan.
The term "compound" as used herein refers to a compound encompassed by the
generic formulae disclosed herein, any subgenus of those generic formulae, and
any forms
of the compounds within the generic and subgeneric formulae, including the
racemates,
stereoisomers, and tautomers of the compound or compounds.
The term "racemates" refers to a mixture of enantiomers.
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The term "stereoisomer" or "stereoisomers" refer to compounds that differ in
the
chirality of one or more stereocenters. Stereoisomers include enantiomers and
diastereomers.
The term "tautomer" refer to alternate forms of a compound that differ in the
position of a proton, such as enol keto and imine enamine tautomers, or the
tautomeric
forms of heteroaryl groups containing a ring atom attached to both a ring NH
moiety and a
ring =N moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and
tetrazoles.
The term "pharmaceutically acceptable salts" is meant to include salts of the
active
compounds which are prepared with relatively nontoxic acids or bases,
depending on the
particular substituents found on the compounds described herein. When
compounds of the
present invention contain relatively acidic functionalities, base addition
salts can be
obtained by contacting the neutral form of such compounds with a sufficient
amount of the
desired base, either neat or in a suitable inert solvent. Examples of salts
derived from
pharmaceutically-acceptable inorganic bases include aluminum, ammonium,
calcium,
copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,
sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable organic bases
include salts of
primary, secondary and tertiary amines, including substituted amines, cyclic
amines,
naturally-occuring amines and the like, such as arginine, betaine, caffeine,
choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines,
theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and
the like.
When compounds of the present invention contain relatively basic
functionalities, acid
addition salts can be obtained by contacting the neutral form of such
compounds with a
sufficient amount of the desired acid, either neat or in a suitable inert
solvent. Examples of
pharmaceutically acceptable acid addition salts include those derived from
inorganic acids
like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric,
hydriodic, or phosphorous acids and the like, as well as the salts derived
from relatively
nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic,
succinic, suberic,
fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,
tartaric,
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methanesulfonic, and the like. Also included are salts of amino acids such as
arginate and
the like, and salts of organic acids like glucuronic or galactunoric acids and
the like (see,
e.g., Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical
Science, 1977,
66, 1-19). Certain specific compounds of the present invention contain both
basic and
acidic functionalities that allow the compounds to be converted into either
base or acid
addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt
with
a base or acid and isolating the parent compound in the conventional manner.
The parent
form of the compound differs from the various salt forms in certain physical
properties,
such as solubility in polar solvents, but otherwise the salts are equivalent
to the parent form
of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are
in a
prodrug form. Prodrugs of the compounds described herein are those compounds
that
readily undergo chemical changes under physiological conditions to provide the
compounds
of the present invention. Additionally, prodrugs can be converted to the
compounds of the
present invention by chemical or biochemical methods in an ex vivo
environment. For
example, prodrugs can be slowly converted to the compounds of the present
invention when
placed in a transdermal patch reservoir with a suitable enzyme or chemical
reagent.
Certain compounds of the present invention can exist in unsolvated forms as
well as
solvated forms, including hydrated forms. In general, the solvated forms are
equivalent to
unsolvated forms and are intended to be encompassed within the scope of the
present
invention. Certain compounds of the present invention may exist in multiple
crystalline or
amorphous forms. In general, all physical forms are equivalent for the uses
contemplated
by the present invention and are intended to be within the scope of the
present invention.
Certain compounds of the present invention possess asymmetric carbon atoms
(optical centers) or double bonds; the racemates, diastereomers, geometric
isomers,
regioisomers and individual isomers (e.g., separate enantiomers) are all
intended to be
encompassed within the scope of the present invention. The compounds of the
present
invention may also contain unnatural proportions of atomic isotopes at one or
more of the
atoms that constitute such compounds. For example, the compounds may be
radiolabeled
with radioactive isotopes, such as for example tritium (3H), iodine-125 (i2sI)
or carbon-14
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(14C). All isotopic variations of the compounds of the present invention,
whether
radioactive or not, are intended to be encompassed within the scope of the
present
invention.
Accordingly, in one embodiment provided is a compound having Formula (I) or a
pharmaceutically acceptable salt, ester, or prodrug thereof:
R'
R3 N =N N P
O N
r)~ I R2 O
(R4)n v I
O
wherein
Ri is halogen;
R2 is hydrogen or halogen;
R3 is selected from the group consisting of -NO2, -NRsaRsb -L-NRsaRSb
-NHC(O)NRsaRsb, -NHC(O)Rs , -NHC(O)Y, Ci_6 alkyl, -CO2H, -C(O)NR5aR5b,
-C(O)NRSaY, -C(O)NH-L-Y, -OH, C1_6 alkoxy, -O-L-NR5aR5b,
-O-L-O-C(O)NRsaRsb, -Y, -O-Y, -O-L-Y, -O-L-Y-L-Y, and -S(O)pRs , wherein
said Ci_6 alkyl and Ci_6 alkoxy are optionally substituted with one to three
substituents selected from R6;
R4 is independently selected from the group consisting of halogen, -OH, -O-L-
Y,
-O-L-NRsaRsb, and C1_6 alkoxy optionally substituted with one to three
substituents selected from R6;
L is Ci-C4 alkylene;
Y is aryl, heteroaryl, or heterocyclic ring, wherein said aryl and heteroaryl
are
optionally substituted with one to three R6 and said heterocyclic ring is
optionally substituted with oxo and optionally with one to three R6 or Rg;
R 5a and Rsb are independently hydrogen or Ci_g alkyl optionally substituted
with one
to three R6, or R5a and Rsb together with the nitrogen atom to which they are
both
attached to form a 5 to 7 membered heterocyclic ring optionally having one
additional ring heteroatom selected from N, NR6, 0, or S(O)p and where said
ring is optionally substituted with one to three substituents selected from
R6;
12
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R5a is Ci_g alkyl optionally substituted with one to three R6;
R6 is independently selected from the group consisting of halogen, -OH, -R', -
OR',
oxo, -SR7, -S(O)R7, -S(O)zR', -SOzNHz, -C(O)NH2, -C(O)R7, -C(NH)R7,
-NHC(O)R7, -NHC(NH)R', -NHC(O)NH2, -CO2H, -NH2, -NHR7, -N(R7)2;
R' is independently C1_6 alkyl;
R8 is -L-heteroaryl optionally substituted with one to three substituents
selected from
R6;
n is 0, 1, or 2;
p is 0, 1, or 2; and
the dashed lines --- are independently single or double bonds;
provided that R3 is not
~\
~-NN-R1 1
where Rii is hydrogen or alkyl.
In another embodiment provided is a compound having Formula (II) or a
pharmaceutically acceptable salt, ester, or prodrug thereof:
Ri
R s N_-N H
/
O N
R2 O
(R4)n
(II)
wherein
Ri is halogen;
R2 is hydrogen or halogen;
R3 is selected from the group consisting of -NO2, -NRsaRsb -L-NR5aR5b
-NHC(O)NRsaRsb, -NHC(O)Rs , -NHC(O)Y, C1_6 alkyl, -CO2H, -C(O)NR5aR5b,
-C(O)NH-L-Y, OH, C1_6 alkoxy, -O-L-NRsaRsb, -O-L-O-C(O)NR5aR5b, -Y, -O-
Y, -O-L-Y, -O-L-Y-L-Y, and -S(O)pRs , wherein said Ci_6 alkyl and Ci_6 alkoxy
are optionally substituted with one to three substituents selected from R6;
R4 is independently selected from the group consisting of halo, OH, -O-L-Y,
-O-L-NRsaRsb, and C1_6 alkoxy optionally substituted with one to three
substituents selected from R6;
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L is Ci-C4 alkylene;
Y is phenyl, heteroaryl, or heterocyclic ring, wherein said phenyl and
heteroaryl are
optionally substituted with one to three R6 and said heterocyclic ring is
optionally substituted with oxo and optionally with one to three R6 or Rg;
Rsa and Rsb are independently hydrogen or Ci_g alkyl optionally substituted
with one
to three R6, or R5a and Rsb together with the nitrogen atom to which they are
both
attached to form a 5 to 7 membered heterocyclic ring optionally having one
additional ring heteroatom selected from N, NR6, 0, or S(O)p and where said
ring is optionally substituted with one to three substituents selected from
R6;
R5a is Ci_g alkyl optionally substituted with one to three R6;
R6 is independently selected from the group consisting of halogen, -OH, -R', -
OR',
oxo, -SR7, -S(O)R7, -S(O)zR', -SOzNHz, -C(O)NH2, -C(O)R7, -C(NH)R7,
-NHC(O)R7, -NHC(NH)R', -NHC(O)NH2, -COzH, -NH2, -NHR7, -N(R7)2;
R' is independently C1_6 alkyl;
R8 is -L-heteroaryl optionally substituted with one to three substituents
selected from
R6;
n is 0, 1, or 2;
p is 0, 1, or 2; and
dashed lines -_ are independently single or double bonds;
provided that R3 is not
\
I_N~N_R1 1
where Rii is hydrogen or alkyl.
As used herein, the wavy line indicates the point of attachment to the rest
of the molecule.
In one embodiment, provided is a compound of Formula (Ia) or a
pharmaceutically
acceptable salt, ester, or prodrug thereof:
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R'
R3 N=N H S
N
N~
p
NI
R2 O
/ (Ia)
wherein R1, R2, and R3 are as previously defined for Formula (I).
In one embodiment, provided is a compound of Formula (Ib) or a
pharmaceutically
acceptable salt, ester, or prodrug thereof:
R'
R s N=N H S
O N
R2 O
N (Ib)
wherein R1, R2, and R3 are as previously defined for Formula (I).
It is contemplated that compounds of Formulas (I), (II), (Ia) and (Ib) will
consistently provide highly active Factor Xa inhibitors.
In some embodiments of the compounds of Formulas (I), (II), (Ia), and (Ib), Ri
is
chlorine.
In some embodiments of Formulas (I), (II), (Ia), and (Ib), R2 is hydrogen.
In some embodiments of Formulas (I), (II), (Ia), and (Ib), R3 is selected from
the
group consisting of -NO2, -NRsaRsb, L-NRsaRsb, -NHC(O)NRsaRsb, -NHC(O)Rs ,
-NHC(O)Y, Ci_6 alkyl, -CO2H, -C(O)NRsaRsb, -C(O)NH-L-Y, -OH, Ci_6 alkoxy, -O-L-
NRsaRsb, -O-L-O-C(O)NRsaRsb, -Y, -O-Y, -O-L-Y, -O-L-Y-L-Y, and -S(O)pRs ,
wherein
said C1_6 alkyl and C1_6 alkoxy are optionally substituted with one to three
substituents
selected from R6.
In some embodiments, R6 is independently selected from the group consisting of
halogen, -OH, -R7, -OR7, -SR7, -S(O)R7, -S(O)2R7, -SO2NH2, -C(O)NH2, -C(O)R7,
-C(NH)R7, -NHC(O)R7, -NHC(NH)R7, -NHC(O)NH2, -CO2H, -NH2, -NHR7, and -N(R7)2.
In some embodiments, R6 is attached to a carbon atom. In some embodiments, R6
is
CA 02674924 2009-07-03
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attached to a nitrogen atom and is independently selected from the group
consisting of -OH,
-R7, -OR7, -S(O)zR', -SOzNHz, -C(O)NH2, -C(O)R7, -C(NH)R7, -NHC(O)R7,
-NHC(NH)R', -NHC(O)NH2, -NH2, -NHR7, and -N(R7)2. In some embodiments, R6 is
attached to a nitrogen atom and is independently selected from the group
consisting of -OH,
-R7, -OR7, -S(O)2R7, -SO2NH2, -C(O)NH2, -C(O)R7, and -C(NH)R7.
In some embodiments, R3 is attached to the phenyl ring through a nitrogen atom
and
is -NO2, -NRsaRsb, -NHC(O)NRsaRsb, -NHC(O)Rs , or -NHC(O)Y. In some aspects,
R3 is
selected from a group consisting of
,CH3
-NOz ~-NHz , ~-N'CH3 ~-N CH3 ~-N'j ~-ND ~ ~-N
> > > > > > > >
-N SO ~-N S02 ~-N ~/ N~O O
H ~ ~/ N4 CH3 ~~ N4 NH
~ v 3 , 3 , 2
O O O O
4 /4 r4 CH3 CH3
I-N NH ~-N N-CH3 -N N~ N NSCH3 ~-N~NH2
~/ ~/ ~/
> > > > >
0 0 NH
,CH3
~-N~N~CH ~-N NH NH2 N~NH CH3 I-NaNH CH3
3 ~
> > > >
OH O O 0
-ND-OH -ND-~
~-N I-N~~NH ~-N~NH2
OH ~ 2 ~ H ~
0 0 0
OH OCH3 /--j OH ~CH3 ~-N ~-N \ N I-N
i
H H N H I I-NH I-NH CH3
> > > > > >
OCH3 CH3 ~OH ~OCH3
/--/ OH O
~-N ~
CH3 NH I-NH CH3 CH3
> > > > >
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CH3
CH3 N-CH3 ~CH3
-iNH2 N'CH3 - ~ NH2 N'CH3
-NH I-N~ CH3 ~-NH -NH
> > > > >
NXH3 NXH3
~-N HN-CH3
~
'CH3 I-N H
~-N /-- O
CH3 CH3 CH3 ~-N~ ~~N
, , and 6 .
In other embodiments, R3 is optionally substituted aryl or heteroaryl. In some
aspects, R3 is selected from a group consisting of
N N- N~ _
J /N I ~ ~ I ~ // ~ C NH 1 ~ ~ NH2 1 ~ ~ OH
, , , , ,
NH2 OH OH CI F
N
N J ~ /N N ~ ~ CI
> > > > >
CH3
i
OCH3 NH2 N-CH3 NHCH3
N
N 1 F ~ C/N ~ C/N ~ C/N
> > > > >
-N N N N NCH3
OH OCH3 NH2 CH3
and
N NXH3
H
In other embodiments, R3 is attached to the phenyl ring through a carbon atom
and is
-L-NRsaRsb, -CO2H, -C(O)NRsaRsb, or -C(O)NH-L-Y. In some embodiments, R3 is
optionally substituted C1_6 alkyl. In some embodiments, R3 is -C(O)NRsaY. In
some
aspects, R3 is selected from a group consisting of
/~ ~ 1/~NCH3 N NO N~ os
lOH JNH2 CH3 ~NH ~O > > > > > > >
0
0 0 O N CH3
~ CH3
~S02 J^SCH3 J^SO2CH3 OH NH2 H CH3
> > > > > > >
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O 0 0 0
N,~OH N~~OH N~iO=CH3 N-,iNH2
H H H H
> > > >
0 0 CH3 O H 0 CH3
"-r NH2 ~\ ~i I ~N~iNCH3 J'\NN,CH3
H 0 ~ H N~CH3 CH3 CH3
> > > >
O
~ ~/\ O O N N O N
N NH2 N" v _NH2 ~ H NH ~
CH3 H OH
> > > > >
0
Vk N 0
O N
NH2 N N, N
H~ N
0 HN-N and H
In other embodiments, R3 is attached to the phenyl ring through an oxygen atom
and
is optionally substituted C1_6 alkoxy, -O-L-NRsaRsb, -O-L-O-C(O)NRsaRsb, -O-Y,
or -O-L-
Y. In some embodiments, R3 is -OH. In some embodiments, R3 is -O-L-Y-L-Y. In
some
aspects, R3 is selected from a group consisting of
CH3 0 0
J-0-CH3 J-O-/ CH3 ~-O-CF3 ~-O---NH JOH ~-O NH2
-OH5 o a ~
N N N
, , , , ,
,CH3
N=CH3 O
-O~N ~-O O _O~ -O NH - ~N CH
~ ~ 3
, , ,
O CH3 O
~-O~N~ H 1-O N-CH3 J-O~N~ H ~-O NH
2 ~ 3
> > > >
~i
O O - ~S-NH2
~-O~S ~-O~SO ~-O~S02 1-O~ S-CH3 ~ O
> > > > >
18
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00 - _,CH3 O. 0
O' u
~ p S_CH3 ~g-NH2 CH3
~-p--N\CH3
> > > >
OH HO OH H2N OH HO NH2 ~OH
~-p~-j ~-p\~--j ~-
0 0
NH2 HN4 HN4 _ NH2
CH3 NH2 ~ O~
> > > >
H2N
H3C >==O
N~O NH OH ~-p~OH
__p~ 1-p~ 1-0---OCH3
> > > > >
OCH3 P-N N
NN
~-p ~- ~- C\/ N - 1-0
/ ~N
IjN N Y-N
~ - N -
~
-O ~ O ~-O ~-O
> > > > >
N O~ H
N N NN IN N/
\ N p _pj-NH
> > > > >
0
O
ll
N/' HN~ ON~ N\ NjN
N CH3 -O> > > >
0 O CH3 CH3 S~ S9\/ CH3
.O ~ N -N
I-O ~- N ~-O I-O ~-O
> > > > >
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/ I
\
N~ NH ~N NX N`Nl
~-O~ -O~ and
O
N
O
~-O
In other embodiments, R3 is attached to the phenyl ring through a sulfur atom
and is
-S(O)pRs . In some aspects, R3 is selected from a group consisting of
O
O O O NH ~NH2 Oõ0 NH
~-S-CH3 ~-S-CH3 -S CH3 ~-S~ 2 ~-S 11 and ~-S~ 2
> > > >
In some aspects of the compounds or compositions of the present invention and
subject to the provisos recited herein, provided is a compound, stereoisomer,
or a
pharmaceutically acceptable salt thereof selected from Table 1.
Table 1
Cmpd Structure Name
ci 5-Chloro-N-((1-(2-(methylamino)-4-
HN N=N s (2-oxopyridin-1(2H)-yl)phenyl)-1H-
1 0 0 1,2,3-triazol-4-yl)methyl)thiophene-
i
N
2-carboxamide
ci 5-Chloro-N-((1-(2-(dimethylamino)-
N N=N ~ ~ 4-(2-oxopyridin-1(2H)-yl)phenyl)-
2 o 1H-1,2,3-triazol-4-
i
N yl)methyl)thiophene-2-carboxamide
ci 5-Chloro-N-((1-(4-(2-oxopyridin-
~ N=N s 1(2H)-yl)-2-(pyrrolidin-l-yl)phenyl)-
3 o
1H-1,2,3-triazol-4-
i o
~ N yl)methyl)thiophene-2-carboxamide
~
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CI 5-Chloro-N-((1-(4-(2-oxopyridin-
N N=N H s 1(2H)-yl)-2-(piperidin-l-yl)phenyl)-
4 0 1H-1,2,3-triazol-4-
/ o
N yl)methyl)thiophene-2-carboxamide
o ol 5-Chloro-N-((1-(2-morpholino-4-(2-
N N=N s~ oxopyridin-1(2H)-yl)phenyl)-1H-
0 N~N 1,2,3-triazol-4-yl)methyl)thiophene-
N O
2-carboxamide
o N 5-Chloro-N-((1-(2-(3-oxopiperazin-
CI
s 1-yl)-4-(2-oxopyridin-1(2H)-
N~ N=N H ~
6 0 N yl)phenyl)-1H-1,2,3-triazol-4-
N / o yl)methyl)thiophene-2-carboxamide
o~N~ 5-Chloro-N-((1-(2-(4-methyl-3-
N N=N H s~ CI oxopiperazin-l-yl)-4-(2-oxopyridin-
7 0 N 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
N / o yl)methyl)thiophene-2-carboxamide
o ~ N ~ N=N 5-Chloro-N-((1-(2-(4-ethyl-3-
cl oxopiperazin-l-yl)-4-(2-oxopyridin-
g
o N d 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
N / 0 yl)methyl)thiophene-2-carboxamide
o ~ 5-Chloro-N-((1-(2-(4-isopropyl-3-
cl oxopiperazin-l-yl)-4-(2-oxopyridin-H o
9 N ~ N=N
N ~ 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
~
o yl)methyl)thiophene-2-carboxamide
21
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ci 5-Chloro-N-((1-(4-(2-oxopyridin-
N N=N s 1(2H)-yl)-2-thiomorpholinophenyl)-
0 x5%1H-1,2,3-triazol-4-
o yl)methyl)thiophene-2-carboxamide
0 5-Chloro-N-((1-(4-(2-oxopyridin-
11
s ci 1(2H)-yl)-2-((1-oxo-
11 N N=N H s )thiomorpholino)phenyl)-1H-1,2,3-
N~~N
0 triazol-4-yl)methyl)thiophene-2-
0
N
carboxamide
p~~ c 5-Chloro-N-((1-(4-(2-oxopyridin-
C ci 1(2H)-yl)-2-((1,1-dioxo-
12 N N~N )thiomorpholino)phenyl)-1H-1,2,3-
0 triazol-4-yl)methyl)thiophene-2-
/ o
carboxamide
N N-((1-(2-(4-Acetylpiperazin-l-yl)-4-
ci (2-oxopyridin-1(2H)-yl)phenyl)-1H-
13 N N=N y s ~
1,2,3-triazol-4-yl)methyl)-5-
o
~ / o chlorothiophene-2-carboxamide
N
HN 5-Chloro-N-((1-(2-(4-(1-
~ Ci iminoethyl)piperazin-l -yl)-4-(2-
14 N N=N H s~ oxopyridin-1(2H)-yl)phenyl)-1H-
0 I N
1,2,3-triazol-4-yl)methyl)thiophene-
i
I N 2-carboxamide
NH2 4-(2-(4-((2-Chlorothiophene-5-
N
N N-N H ci carboxamido)methyl)-1H-1,2,3-
S~
o N~~N ~ triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N o yl)phenyl)piperazine-l-carboxamide
22
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Noo' 5-Chloro-N-((1-(2-(4-
6 Ci (dimethylamino)piperidin- l -yl)-4-(2-
16 0 ~ N~~N H ~V oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-
/
2-carboxamide
NHZ
N-((1-(2-(4-Aminopiperidin-l -yl)-4-
N N ci (2-oxohYridin-1 (2H)-Y1)hhenY1)- 1H-
cN H g
17 o N 1,2,3-triazol-4-yl)methyl)-5-
N& 0 chlorothiophene-2-carboxamide
o N-((1-(2-(4-Acetamidopiperidin-l-
"Njk**' yl)-4-(2-oxopyridin-1(2H)-
6 ci yl)phenyl)-1H-1,2,3-triazol-4-
1g N N=N H S~
o N~,N ~ yl)methyl)-5-chlorothiophene-2-
N O
carboxamide
NH N-((1-(2-(4-Acetamidinopiperidin-l-
HNjkl yl)-4-(2-oxopyridin-1(2H)-
6 cl yl)phenyl)-1H-1,2,3-triazol-4-
19 N N_N H S~
o 4~,N ~ yl)methyl)-5-chlorothiophene-2-
~ o carboxamide
0
HNA NH2 1-(1-(2-(4-((2-Chlorothiophene-5-
6 ci carboxamido)methyl)-1H-1,2,3-
20 N N~HIP triazol-l-yl)-5-(2-oxopyridin-1(2H)-
0 yl)phenyl)piperidin-4-yl)urea
I N
OH 5-Chloro-N-((1-(2-(4-
6 ci hydroxypiperidin-l-yl)-4-(2-
21 N N=N N ~~ oxopyyridin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-
o
N
I / 2-carboxamide
23
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OH 5-Chloro-N-((1-(2-((R)-3-
~H cI hydroxypiperidin-l-yl)-4-(2-
N N=N 22 oxopyridin-1(2H)-yl)phenyl)-1H-
J5..N'SLJ1.JZ
o 1,2,3-triazol-4-yl)methyl)thiophene-
N
~ 2-carboxamide
H 5-Chloro-N-((1-(2-((S)-3-
CTIIOH cI hydroxypiperidin-l-yl)-4-(2-
N N-N H S
23 ni - N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
o o 1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
CozH 1-(2-(4-((2-Chlorothiophene-5-
cl carboxamido)methyl)-IH-1,2,3-
N=N N~N ~~ triazol-l-yl)-5-(2-oxopyridin-1(2H)-
o yl)phenyl)piperidine-4-carboxylic
N acid
O NH2 1-(2-(4-((2-Chlorothiophene-5-
cl carboxamido)methyl)-1H-1,2,3-
25 N N-N H S~
o ~ N~,N ~ triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N o yl)phenyl)piperidine-4-carboxamide
I~
oH 5-Chloro-N-((1-(2-(2-
CI hydroxyethylamino)-4-(2-
NH N=N H S
26 N~~N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
O
p 1,2,3-triazol-4-yl)methyl)thiophene-
N
~ 2-carboxamide
0 5-Chloro-N-((1-(2-(2-
` CI
methoxyethylamino)-4-(2-
NH N=N H S
27 N~N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
O
~ , p 1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
24
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oH 5-Chloro-N-((1-(2-((2-
N .1*1 N=N cl hydroxyethyl)(methyl)amino)-4-(2-
S
28 o N~~N oxopyridin-1(2H)-yl)phenyl)-1H-
N H
o 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
0 5-Chloro-N-((1-(2-((2-
N .11, N-N cl methoxyethyl)(methyl)amino)-4-(2-
S
29 N -_1 NH oxopyridin-1(2H)-yl)phenyl)-1H-
o ~/~
0 1,2,3-triazol-4-yl)methyl)thiophene-
N
~ 2-carboxamide
NH2 cl N-((1-(2-(2-Aminoethylamino)-4-(2-
NH N=N H s oxopyridin-1(2H)-yl)phenyl)-1H-
30 O N~N 1,2,3-triazol-4-yl)methyl)-5-
N chlorothiophene-2-carboxamide
~ o
~ 5-Chloro-N-((1-(2-(2-
CN
ci (dimethylamino)ethylamino)-4-(2-
NH N-N s~ oxopyridin-1(2H)-yl)phenyl)-1H-
31
0 N o
1,2,3-triazol-4-yl)methyl)thiophene-
i
N
2-carboxamide
I 5-Chloro-N-((1-(2-((2-
N
ci (dimethylamino)ethyl)(methyl)amino
32 N N~N p )-4-(2-oxopyridin-1(2H)-yl)phenyl)-
0 1H-1,2,3-triazol-4-
O
N yl)methyl)thiophene-2-carboxamide
5-Chloro-N-((1-(2-(3-
~OH ci hydroxypropylamino)-4-(2-
NH N-N H S
33 0 ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N ~ 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
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/ 5-Chloro-N-((1-(2-(3-
cl
methoxypropylamino)-4-(2-
NH N-N H s
34 0 N~iN oxopyridin-1(2H)-yl)phenyl)-1H-
N / 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-((3-
~OH ci hydroxypropyl)(methyl)amino)-4-(2-
~
N N=N H s
35 0 N~iN oxopyridin-1(2H)-yl)phenyl)-1H-
N ( 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-((3-
cl methoxypropyl)(methyl)amino)-4-(2-
N N-N H s
36 0 N~iN oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
(NH2 cl N-((1-(2-(3-Aminopropylamino)-4-
NH N-N H s (2-oxopyridin-1(2H)-yl)phenyl)-1H-
37 0 I N~N
1,2,3-triazol-4-yl)methyl)-5-
/ 0
N chlorothiophene-2-carboxamide
~
N 5-Chloro-N-((1-(2-(3-
I cl (dimethylamino)propylamino)-4-(2-
NH N-N H s
38 0 N~~N oxopyridin-1(2H)-yl)phenyl)-1H-
N O 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
Noll 5-Chloro-N-((1-(2-((3-
cl (dimethylamino)propyl)(methyl)amin
39 eN .01 N_=/N~ H o)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
0 I Nv `~N
1H-1,2,3-triazol-4-
N / O
yl)methyl)thiophene-2-carboxamide
26
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NH 5-Chloro-N-((1-(2-(methyl(3-
ci (methylamino)propyl)amino)-4-(2-
40 eN .01 N=N H s~ oxopyridin-1(2H)-yl)phenyl)-1H-
0 N~,N ~
1,2,3-triazol-4-yl)methyl)thiophene-
N O
2-carboxamide
H 5-Chloro-N-((1-(2-(methyl(2-
N
ci (methylamino)ethyl)amino)-4-(2-
i
H-
41 N NA N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
o ,/,
1,2,3-triazol-4-yl)methyl)thiophene-
2-carboxamide
N ci N-((1-(2-(1H-Imidazol-l-yl)-4-(2-
N N=N H s oxopyridin-1(2H)-yl)phenyl)-1H-
42 0 1,2,3-triazol-4-yl)methyl)-5-
/ o
chlorothiophene-2-carboxamide
CI 5-Chloro-N-((1-(4-(2-oxopyridin-
O N N=N H 5~ 1(2H)-yl)-2-(2-oxopyrrolidin-l-
43 p I Nv `~N \
yl)phenyl)-1 H- 1,2,3 -triazol-4-
N O
yl)methyl)thiophene-2-carboxamide
ci 5-Chloro-N-((1-(2-nitro-4-(2-
N02 ~~~ ~~ oxopyridin-1(2H)-yl)phenyl)-1H-
44 0 0 1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
ci N-((1-(2-Amino-4-(2-oxopyridin-
N~2 N=N N ~~ 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
45 0 ~~ o yl)methyl)-5-chlorothiophene-2-
N
carboxamide
NH2 ci 1-(2-(4-((2-Chlorothiophene-5-
0--4-NH N=N H carboxamido)methyl)-1H-1,2,3-
46 o N
triazol-l-yl)-5-(2-oxopyridin-1(2H)-
/
~ N yl)phenyl)urea
27
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ci N-((1-(2-Acetamido-4-(2-
OJ-NH N=N H oxopyridin-1(2H)-yl)phenyl)-1H-
N~~
47 0 N 1,2,3-triazol-4-yl)methyl)-5-
~
N
chlorothiophene-2-carboxamide
N
N-(2-(4-((2-Chlorothiophene-5-
ci carboxamido)methyl)-1H-1,2,3-
48 O NH N-N H S
o ~
N triazol-l-yl)-5-(2-oxopyridin-1(2H)-
~ o yl)phenyl)isonicotinamide
I N
N
N-(2-(4-((2-Chlorothiophene-5-
ci carboxamido)methyl)-1H-1,2,3-
49 O NH N-N H S~
o ~ N triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N o yl)phenyl)nicotinamide
ci 5-Chloro-N-((1-(2-(methylthio)-4-(2-
s N=N ~ s oxopyridin-1(2H)-yl)phenyl)-1H-
50 0 1,2,3-triazol-4-yl)methyl)thiophene-
i
N
2-carboxamide
ci 5-Chloro-N-((1-(2-(methylsulfoxy)-
'9'~o N=N H s 4-(2-oxopyridin-1(2H)-yl)phenyl)-
51 0 N
1H-1,2,3-triazol-4-
o
~ yl)methyl)thiophene-2-carboxamide
o ci -(2-(methylsulfonyl)-
N=N =o ~ 4-(2-oxopyridin-1(2H)-yl)phenyl)-
52 0 1H-1,2,3-triazol-4-
i O
N yl)methyl)thiophene-2-carboxamide
NH2 ci N-((1-(2-(2-Aminoethylthio)-4-(2-
s N=N H s~ oxopyridin-1(2H)-yl)phenyl)-1H-
53 0 N 1,2,3-triazol-4-yl)methyl)-5-
N chlorothiophene-2-carboxamide
~ o
28
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CNH2 ci N-((1-(2-(2-Aminoethylsulfoxy)-4-
s'o N=N H s (2-oxopyridin-1(2H)-yl)phenyl)-1H-
54 0 &NO~,,N 1,2,3-triazol-4-yl)methyl)-5-
N o chlorothiophene-2-carboxamide
NHz CI N-((1-(2-(2-Aminoethylsulfonyl)-4-
s~0
N_N H s (2-oxopyridin-1(2H)-yl)phenyl)-1H-
55 0 N 1,2,3-triazol-4-yl)methyl)-5-
~ N o chlorothiophene-2-carboxamide
ci 5-Chloro-N-((1-(2-methoxy-4-(2-
o N_N H s oxopyridin-1(2H)-yl)phenyl)-1H-
56 0 NN 1,2,3-triazol-4-yl)methyl)thiophene-
N 2-carboxamide
H 5-Chloro-N-((1-(4-(2-oxopyridin-
N ci 1(2H)-yl)-2-(piperidin-4-
57 O N=N
0 S
N~~N H yloxy)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
0 N-((1-(2-(1-Acetylpiperidin-4-
AaS cI yloxy)-4-(2-oxopyridin-1(2H)-
o - s
58 ~~H yl)phenyl)-1H-1,2,3-triazol-4-
o yl)methyl)-5-chlorothiophene-2-
i o
N
carboxamide
0 4-(2-(4-((2-Chlorothiophene-5-
H2NA, CLO cI carboxamido)methyl)-1H-1,2,3-
59 N-N N d triazol-l-yl)-5-(2-oxopyridin-1(2H)-
o yl)phenoxy)piperidine-l-
N o
carboxamide
29
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5-Chloro-N-((1-(2-(1-
N ci
methylpiperidin-4-yloxy)-4-(2-
methylpiperidin-4-yloxy)-4-(2-
0 N-N H
60 0 oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
~ 5-Chloro-N-((1-(2-(1-
ao CI isopropylpiperidin-4-yloxy)-4-(2-
61 N=N N oxopyyridin-1(2H)-yl)phenyl)-1H-
0 1,2,3-triazol-4-yl)methyl)thiophene-
i o
I N 2-carboxamide
0
H 5-Chloro-N-((1-(2-(2-oxopiperidin-4-
N ci yloxy)-4-(2-oxopyridin-1(2H)-
0 S
62 O N- N N H yl)phenyl)-1H-1,2,3-triazol-4-
\
N i 0 yl)methyl)thiophene-2-carboxamide
a,- 5-Chloro-N-((1-(4-(2-oxopyridin-
CI
0 g~ 1(2H)-yl)-2-(pyridin-4-
O N=N H
63 N~~N v yloxy)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
N 5-Chloro-N-((1-(4-(2-oxopyridin-
.
v ~ 0 N_N s cI 1(2H)-yl)-2-(pyridin-3-
64 N~~N yloxy)phenyl)-1H-1,2,3-triazol-4-
o
NI \
i 0 yl)methyl)thiophene-2-carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
O N-N H ci 1(2H)-yl)-2-(tetrahydro-2H-
65 0 v N~iN thiopyran-4-yloxy)phenyl)-1H-1,2,3-
N 0 triazol-4-yl)methyl)thiophene-2-
carboxamide
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0 5-Chloro-N-((1-(4-(2-oxopyridin-
0~ Cl 1(2H)-yl)-2-(1,1-dioxo-tetrahydro-
66 o N=N N 2H-thiopyran-4-yloxy)phenyl)-1 H-
o
1,2,3-triazol-4-yl)methyl)thiophene-
2-carboxamide
/ \ 5-Chloro-N-((1-(2-(3-(1,3-
o N o dioxoisoindolin-2-yl)propoxy)-4-(2-
67 c~ oxopYridin-1 (2H)-yl)phenyl)- 1H-
~O N=N S
o N 1,2,3-triazol-4-yl)methyl)thiophene-
~ N ~ 2-carboxamide
NH2 ci N-((1-(2-(3-Aminopropoxy)-4-(2-
~o N=N H S ~ oxopyridin-1(2H)-yl)phenyl)-1H-
6g 0 ~
1,2,3-triazol-4-yl)methyl)-5-
o
N chlorothiophene-2-carboxamide
0
HN CI N-((1-(2-(3 -Acetamidopropoxy)-4-
(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
o S
69 O N-N N~~N H ~ 1,2,3-triazol-4-yl)methyl)-5-
0 chlorothiophene-2-carboxamide
0
A 1-(3-(2-(4-((2-Chlorothiophene-5-
HN NHZ CI
carboxamido)methyl)-1 H-1,2,3-
O N=N H
70 0 N ~ triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N 0 yl)phenoxy)propyl)urea
ci N-((1-(2-(2-Aminoethoxy)-4-(2-
HzN,,~~o N=N ~ ~\ oxopyridin-1(2H)-yl)phenyl)-1H-
71 0 ~ ~ o 1,2,3-triazol-4-yl)methyl)-5-
i
N
chlorothiophene-2-carboxamide
31
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o~/ ci N-((1-(2-(2-Acetamidoethoxy)-4-(2-
HN~,--,o N_N H s~ oxopyridin-1(2H)-yl)phenyl)-1H-
72 O 1,2,3-triazol-4-yl)methyl)-5-
I N chlorothiophene-2-carboxamide
O. NH2 1-(2-(2-(4-((2-Chlorothiophene-5-
1 ci
HN,,,~o N=N H s~ carboxamido)methyl)-1H-1,2,3-
73 0 triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N o yl)phenoxy)ethyl)urea
OH ci 5-Chloro-N-((1-(2-(3-
("~o NcN H s ~ hydroxypropoxy)-4-(2-oxopyridin-
74 O N % `~ N
1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
N ( o yl)methyl)thiophene-2-carboxamide
ci 5-Chloro-N-((1-(2-(2-
HO--~o ~~~ hydroxyethoxy)-4-(2-oxopyridin-
75 0 0 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
N yl)methyl)thiophene-2-carboxamide
ci 5-Chloro-N-((1-(2-(2-
-'0'-"'0 N=N ~ methoxyethoxy)-4-(2-oxopyridin-
76 0 ~ 0 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
N yl)methyl)thiophene-2-carboxamide
~ ci 5-Chloro-N-((1-(2-(3-
O N=N H s methoxypropoxy)-4-(2-oxopyridin-
77 0 ~ ~ N 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
~
N yl)methyl)thiophene-2-carboxamide
OH ci 5-Chloro-N-((1-(2-((R)-2,3-
~_ N=N H ~ dihydroxypropoxy)-4-(2-oxopyridin-
78 0 OH ~ N~,N Os
1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
I
N yl)methyl)thiophene-2-carboxamide
32
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OH cI 5-Chloro-N-((1-(2-((s)-2,3-
ll--~ O N=N H dihydroxypropoxy)-4-(2-oxopyridin-
79 0 OH ~ N
1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
~i
N yl)methyl)thiophene-2-carboxamide
5-Chloro-N-((1-(2-(2-
~ Ke--Io N=N H s ~ I (methylsulfonyl)ethoxy)-4-(2-
80 0 Noxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-(2-
H N%~s~~o N=N ol (aminosulfonyl)ethoxy)-4-(2-
2 H
81 0 oxopyridin-1(2H)-yl)phenyl)-1 H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-(2-
O~ O CI
~s~ce^1o N_N H s (ethylsulfonyl)ethoxy)-4-(2-
82 0 oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-(3-
CI
N_N H (methylsulfonyl)propoxy)-4-(2-
0 0 N oxopyridin-1(2H)-yl)phenyl)-1H-
83 0
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
cl 5-Chloro-N-((1-(2-(3-
H2N, ^-~ o N=N aminosulfon 1 ro ox 4- 2-
o=ko H ( Y)p p Y)- (
84 0 o oxopyridin-1(2H)-yl)phenyl)-1H-
N 1,2,3-triazol-4-yl)methyl)thiophene-
2-carboxamide
33
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5-Chloro-N-((1-(2-(2-
N,-.,o N_N H s (dimethylamino)ethoxy)-4-(2-
I
85 0 N~N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N ~ 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(2-(2-
(dimethyl(dimethylamino)amino)eth
N. i N ci
O N-N H S ~
86 0 ~ ~ N oxy)-4-(2-oxopyridin-1(2H)-
N ~ yl)phenyl)-1H-1,2,3-triazol-4-
-triazol-4-
yl)methyl)thiophene-2-carboxamide
5-Chloro-N-((1-(2-(2-
H CI
N_,e~-,o N=N H s (methylamino)ethoxy)-4-(2-
=
87 0 ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
N0 N=N s C1 1(2H)-yl)-2-(2-(pyrrolidin-l-
88 o N~N yl)ethoxy)phenyl)-1H-1,2,3-triazol-
N l o 4-yl)methyl)thiophene-2-
carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
N~~ cI 1(2H)-yl)-2-(2-(piperidin-l-
0 O N-N H S ~
gg N~~N yl)ethoxy)phenyl)-1H-1,2,3-triazol-
N o 4-yl)methyl)thiophene-2-
carboxamide
o~ ol 5-Chloro-N-((1-(2-(2-
~N,,^,o N=N H s ~ morpholinoethoxy)-4-(2-oxopyridin-
90 o N
1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
-triazol-4-
0
N yl)methyl)thiophene-2-carboxamide
34
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N 5-Chloro-N-((1-(4-(2-oxopyridin-
~ 0 N=N ~I 1(2H)-yl)-2-(2-(pyridin-4-
91 o N yl)ethoxy)phenyl)-1H-1,2,3-triazol-
N o 4-yl)methyl)thiophene-2-
carboxamide
5-Chloro-N-((1-(2-(3-
cI
s (dimethylamino)propoxy)-4-(2-
N"**~o N=N H ~
92 0 N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
93 s~ I 1(2H)-yl)-2-(3-(pyrrolidin-l-
~~o N=N H
0 N~~N ~ yl)propoxy)phenyl)-1H-1,2,3-triazol-
N ~ 0 4-yl)methyl)thiophene-2-
carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
CI
--~~O N=N H s~ 1(2H)-yl)-2-(3-(piperidin-l-
94 0 N~,N ~ yl)propoxy)phenyl)-1H-1,2,3-triazol-
0 4-yl)methyl)thiophene-2-
carboxamide
5-Chloro-N-((1-(2-(3-
r'N'*--'o N_N s cI morpholinopropoxy)-4-(2-
~ H ~
5NyJ) oxopyridin-1(2H)-yl)phenyl)-1H-
0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
ci 2-(2-(4-((2-Chlorothiophene-5-
HO
,Tro ~~~ ~\ carboxamido)methyl)-1H-1,2,3-
96 0 ~~ 0 triazol-l-yl)-5-(2-oxopyridin-1(2H)-
N yl)phenoxy)acetic acid
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ci N-((1-(2-(2-Amino-2-oxoethoxy)-4-
HZN
If"**, o N=N ~ ~~ (2-oxopyridin-1(2H)-yl)phenyl)-1H-
97 0 ~
~ 1,2,3-triazol-4-yl)methyl)-5-
i o
chlorothiophene-2-carboxamide
N=N N-((1-(2-((1 H-Tetrazol-5 -
HN~N
ci yl)methoxy)-4-(2-oxopyridin-1(2H)-
98 o N=N ~ 1~ yl)phenyl)-1H-1,2,3-triazol-4-
o yl)methyl)-5-chlorothiophene-2-
i
I N
carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
F
1(2H)-yl)-2-
F>L,O N=N g ci
99 0 ~ 4~~ ~ (~fluoromethoxy)phenyl)-1H-1,2,3-
N ~ i 0 triazol-4-yl)methyl)thiophene-2-
carboxamide
ci 2-(4-((2-Chlorothiophene-5-
Ho o ~ ~ N s carboxamido)methyl)-1H-1,2,3-
100 0 triazol-l-yl)-5-(2-oxopyridin-1(2H)-
~ yl)benzoic acid
ci N-((1-(2-Carbamoyl-4-(2-
z
H ~\ oxopyridin-1(2H)-yl)phenyl)-1H-
l01 0 1,2,3-triazol-4-yl)methyl)-5-
o
N
chlorothiophene-2-carboxamide
~ ci 5-Chloro-N-((1-(2-
HN o N=N s (methylcarbamoyl)-4-(2-oxopyridin-
102
0 N 0 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
N yl)methyl)thiophene-2-carboxamide
36
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5-Chloro-N-((1-(2-
N o N_N H s ~ ~ (dimethylcarbamoyl)-4-(2-
103 0 N ~ oxopyridin-1(2H)-yl)phenyl)-1 H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
N-((1-(2-((2-
Ho~~N o N_N H s~~ Hydroxyethyl)carbamoyl)-4-(2-
104 0 N N oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
N-((I-(2-((3-
H ~
o N=N H s~ Hydroxypropyl)carbamoyl)-4-(2-
105 0 ~ N ~N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N ~ ~ 0 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
-(2-((2-
H ci
~~ ~ N=N H s Methoxyethyl)carbamoyl)-4-(2-
~
106 0 N oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
-(2-((2-
H ci
HzNo ~N 0 N_N H Aminoethyl)carbamoyl)-4-(2-
107 107 0 ~ N S~ oxopyridin-1(2H)-yl)phenyl)-1 H-
N 0
1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
N-((1-(2-((2-Amino-2-
0
HN~N oN_N s
108 0 ~~ oxoethyl)carbamoyl)-4-(2-
~ NN oxopyridin-1(2H)-yl)phenyl)-1H-
N o 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
37
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N-((1-(2-((2-
H
N~N O N_N s ci (Dimethylamino)ethyl)carbamoyl)-4-
~ H ~
109 0 ~ ~ N~N ~ (2-oxopyridin-1(2H)-yl)phenyl)-1H-
N / O 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
CI 5-Chloro-N-((1-(2-(methyl(2-
~
~N O N_N g (methylamino)ethyl)carbamoyl)-4-
H ~
110 O ~ (2-oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
2-carboxamide
5-Chloro-N-((1-(2-((2-
N~~ O N=N g ~~ (dimethylamino)ethyl)(methyl)carba
N~~N ~ moyl)-4-(2-oxopyridin-1(2H)-
0
111
N / 0 yl)phenyl)-1H-1,2,3-triazol-4-
~ yl)methyl)thiophene-2-carboxamide
H ci N-((1-(2-(3-aminopropylcarbamoyl)-
N
HzN~/,,_,
~~ 4-(2-oxopyridin-1(2H)-yl)phenyl)-
~ H
112 0
1H-1,2,3-triazol-4-yl)methyl)-5-
O
N
chlorothiophene-2-carboxamide
HN') ci 5-Chloro-N-((1-(4-(2-oxopyridin-
~N O N=N H S~ 1(2H)-yl)-2-(piperazine-l-
113 0 L~', N~,N ~
carbonyl)phenyl)-1 H-1,2,3-triazol-4-
O
N yl)methyl)thiophene-2-carboxamide
HN') ci 5-Chloro-N-((1-(2-(2-oxopiperazine-
0--4~ N 0 N=N H 4-carbonyl)-4-(2-oxopyridin-1(2H)-
114 0
yl)phenyl)-1 H-1,2,3 -triazol-4-
N
yl)methyl)thiophene-2-carboxamide
38
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HO 5-Chloro-N-((1-(2-(4-
N O ~~ hydroxypiperidine-l-carbonyl)-4-(2-
N-N H S ~
H-
115 N~N oxopyridin-1(2H)-yl)phenyl)-1H-
O
~ , p 1,2,3-triazol-4-yl)methyl)thiophene-
I N
2-carboxamide
0
1-(2-(4-((5-Chlorothiophene-2-
H2N
sci carboxamido)methyl)-1H-1,2,3-
N 0 N_N ~
116 N~~N triazol-l-yl)-5-(2-oxopyridin-1(2H)-
o
N ~ o yl)benzoyl)piperidine-4-carboxamide
N-((1-(2-(((1 H-Tetrazol-5-
N-NH
N,~~N o ci yl)methyl)carbamoyl)-4-(2-
N-N H
117 p ~ N~iN oxopyridin-1(2H)-yl)phenyl)-1H-
N ~ O 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
NN ~ o N=N H S~~ 1(2H)-yl)-2-(pyridin-4-
118 O ~ N~N ylcarbamoyl)phenyl)-1H-1,2,3-
N 0 triazol-4-yl)methyl)thiophene-2-
carboxamide
ci 5-Chloro-N-((1-(2-(hydroxymethyl)-
HO
~ ~\ 4-(2-oxopyridin-1(2H)-yl)phenyl)-
119 0 1H-1,2,3-triazol-4-
O
N yl)methyl)thiophene-2-carboxamide
ci N-((1-(2-(Aminomethyl)-4-(2-
HZN N=N H ~\ oxopyridin-1(2H)-yl)phenyl)-1H-
120 0 1,2,3-triazol-4-yl)methyl)-5-
O
N
chlorothiophene-2-carboxamide
39
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5-Chloro-N-((1-(2-
N N_N H s ~ ~ ((dimethylamino)methyl)-4-(2-
121 0 N oxopyridin-1(2H)-yl)phenyl)-1H-
N 0 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
ci 5-Chloro-N-((1-(4-(2-oxopyridin-
~ NcN s 1(2H)-yl)-2-(piperidin-l-
122 0 N
ylmethyl)phenyl)-1 H-1,2,3-triazol-4-
o
N yl)methyl)thiophene-2-carboxamide
ci 5-Chloro-N-((1-(2-
.-Is N=N ~ (methylthiomethyl)-4-(2-oxopyridin-
123 0 0 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
-triazol-4-
N yl)methyl)thiophene-2-carboxamide
5-Chloro-N-((1-(2-
0
(methylsulfonylmethyl)-4-(2-
N_N H s i
124 0 N oxopyridin-1(2H)-yl)phenyl)-1H-
N o 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
~ N ci 5-Chloro-N-((l-(4-(2-oxopyridin-
~ N_N H s 1(2H)-yl)-2-(pyridin-4-yl)phenyl)-
125 0 1H-1,2,3-triazol-4-
N ~ 0 yl)methyl)thiophene-2-carboxamide
N ci 5-Chloro-N-((1-(4-(2-oxopyridin-
N_N H s 1(2H)-yl)-2-(pyridin-3-yl)phenyl)-
126 0 N/,,N
1H-1,2,3-triazol-4-
o
N yl)methyl)thiophene-2-carboxamide
N~^N oi 5-Chloro-N-((1-(4-(2-oxopyridin-
N=N H s~ 1(2H)-Y1)-2-~YY'imidin-5-Y1)phenY1)-
~\
127 0 ~/N
1H-1,2,3-triazol-4-
i o
N yl)methyl)thiophene-2-carboxamide
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~ NH ci 5-Chloro-N-((1-(4-(2-oxopyridin-
N N=N H s 1(2H)-yl)-2-(1H-pyrazol-3-
128 O
yl)phenyl)-1 H- 1,2,3 -triazol-4-
N O
yl)methyl)thiophene-2-carboxamide
NH2 5-Chloro-N-((1-(4-(2-oxopyridin-
~ ci 1(2H)-yl)-2-((4-
/
129 N~N ~\ aminophenyl)phenyl)-1H-1,2,3-
0 triazol-4-yl)methyl)thiophene-2-
O
N
carboxamide
OH 5-Chloro-N-((1-(4-(2-oxopyridin-
~ ci 1(2H)-yl)-2-((4-
130 N~N ~~ hydroxyphenyl)phenyl)-1H-1,2,3-
0 triazol-4-yl)methyl)thiophene-2-
N
carboxamide
NH2 5-Chloro-N-((1-(4-(2-oxopyridin-
I ~ c~ 1(2H)-yl)-2-((3-
N-N H s
131 N~~N aminophenyl)phenyl)-1H-1,2,3-
o ~
~ / p triazol-4-yl)methyl)thiophene-2-
N
carboxamide
oH 5-Chloro-N-((1-(4-(2-oxopyridin-
I c~ 1(2H)-yl)-2-((3-
N-N H s
132 NN hydroxyphenyl)phenyl)-1H-1,2,3-
o
/ p triazol-4-yl)methyl)thiophene-2-
N
carboxamide
N cl ci 5-Chloro-N-((1-(2-(2-chloropyridin-
N_N H s 4-yl)-4-(2-oxopyridin-1(2H)-
133 0 NN yl)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
41
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N F ci 5-Chloro-N-((1-(2-(2-fluoropyridin-
NcN H s 4-yl)-4-(2-oxopyridin-1(2H)-
134 0 N yl)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
ci
5-Chloro-N-((1-(2-(6-chloropyridin-
N
3-yl)-4-(2-oxopyridin-1(2H)-
N_N H s ~ i
135 0 NN yl)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
F
5-Chloro-N-((1-(2-(6-fluoropyridin-
N
3-yl)-4-(2-oxopyridin-1(2H)-
N=N H ci
136
o NN yl)phenyl)-1H-1,2,3-triazol-4-
N 0 yl)methyl)thiophene-2-carboxamide
N OH 5-Chloro-N-((1-(2-(2-
~ ~ ci
hydroxypyridin-4-yl)-4-(2-
N-N H s
137 NN oxopyridin-1(2H)-yl)phenyl)-1H-
o
N o 1,2,3-triazol-4-yl)methyl)thiophene-
2-carboxamide
N 011*% 5-Chloro-N-((1-(2-(2-
~ CI methoxYhYridin-4-Y1)-4-(2-
~ /
N =N N S
138 ,,,~ oxopyridin-1(2H)-yl)phenyl)-1H-
O
1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
~ NH2 ci N-((1-(2-(2-Aminopyridin-4-yl)-4-
~ NcN H s (2-oxopyridin-1(2H)-yl)phenyl)-1H-
139 0 N~N 1,2,3-triazol-4-yl)methyl)-5-
N 0 chlorothiophene-2-carboxamide
42
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~ 5-Chloro-N-((1-(2-(2-
N N
ci (dimethylamino)pyridin-4-yl)-4-(2-
N=N 140 N ~~ oxopyridin-1(2H)-yl)phenyl)-1H-
o 1,2,3-triazol-4-yl)methyl)thiophene-
i o
N
2-carboxamide
H 5-Chloro-N-((1-(2-(2-
N N
ci (methylamino)pyridin-4-yl)-4-(2-
141 N- 1 N ~~ oxopyridin-1(2H)-yl)phenyl)-1H-
o
0 1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
OH 5-Chloro-N-((1-(2-(6-
~ ~ N ci hydroxypyridin-3-yl)-4-(2-
i
142 N~N ~\ oxopyridin-1(2H)-yl)phenyl)-1H-
o 1,2,3-triazol-4-yl)methyl)thiophene-
i o
N 2-carboxamide
o~ 5-Chloro-N-((1-(2-(6-
~ N ci methoxypyridin-3-yl)-4-(2-
N=N H s ~ oxopyridin-1(2H)-yl)phenyl)-1H-
143
0 N~~N ~
1,2,3-triazol-4-yl)methyl)thiophene-
i o
N 2-carboxamide
NH2
N-((1-(2-(6-Aminopyridin-3-yl)-4-
N
N_N o s ci i (2-oxopyridin-1(2H)-yl)phenyl)-1H-
144 1,2,3-triazol-4-yl)methyl)-5-
N ~ 0 chlorothiophene-2-carboxamide
N 5-Chloro-N-((1-(2-(6-
~ N ci (dimethylamino)pyridin-3-yl)-4-(2-
145 N=N N s oxopYr'idin-1 (2H)-yl)phenyl)- 1H-
o 1,2,3-triazol-4-yl)methyl)thiophene-
o
N 2-carboxamide
43
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NH 5-Chloro-N-((1-(2-(6-
~ N ci (methylamino)pyridin-3-yl)-4-(2-
N=N H s ~ oxopyridin-1(2H)-yl)phenyl)-1H-
146
IQZI 1,2,3-triazol-4-yl)methyl)thiophene-
0& o
N
2-carboxamide
N-((1-(2-(3-Amino-3-
HzN~N ~
0 N=N H s~ oxopropylcarbamoyl)-4-(2-
147 0 o N ~ oxopyridin-1(2H)-yl)phenyl)-1H-
N 1,2,3-triazol-4-yl)methyl)-5-
~ chlorothiophene-2-carboxamide
N N-((1-(2-(2-(1 H-Imidazol-l-
ci yl)ethoxy)-4-(2-oxopyridin-1(2H)-
N=N s 1 hen 1-1H-1 2 3-triazol-4-
148 N~ N ~ Y)p Y) ,,
0 ~ ~/~ yl)methyl)-5-chlorothiophene-2-
o
N carboxamide
N ~ ~ 5-Chloro-N-((1-(4-(2-oxopyridin-
~ ci 1(2H)-yl)-2-(2-(pyridin-4-
149 o N=N H s~ yl)ethoxy)phenyl)-1H-1,2,3-triazol-
0 ~
4-yl)methyl)thiophene-2-
0
~ N carboxamide
~~ 3-(2-(4-((5-Chlorothiophene-2-
Ci
rN o o N=N s carboxamido)methyl)-1H-1,2,3-
150 0 N~N triazol-1-yl)-5-(2-oxopyridin-1(2H)-
~ N o yl)phenoxy)propyl morpholine-4-
carboxylate
~N ci 5-Chloro-N-((1-(4-(2-oxopyridin-
i I
o NcN H s 1(2H)-yl)-2-(pyridin-2-
151 0 N yloxy)phenyl)-1H-1,2,3-triazol-4-
N o yl)methyl)thiophene-2-carboxamid
44
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O OH CI 2-(2-(4-((5-Chlorothiophene-2-
~T O N_N H S~ carboxamido)methyl)-5-iodo-lH-
152 O N 1,2,3-triazol-l-yl)-5-(2-oxopyridin-
O 1(2H)-yl)phenoxy)acetic acid
OH 5-Chloro-N-((1-(2-(3-
CI hydroxypropoxy)-4-(2-oxopyridin-
153 O N=N H S 1(2H)-yl)phenyl)-5-iodo-lH-1,2,3-
I N_ /~ 'N
0
v triazol-4-yl)methyl)thiophene-2-
N / ~ O
carboxamide
OH 5-Chloro-N-((1-(2-((R)-2,3-
OH
ci dihydroxypropoxy)-4-(2-oxopyridin-
154 O N_N H 1(2H)-yl)phenyl)-5-iodo-lH-1,2,3-
0
triazol-4-yl)methyl)thiophene-2-
N
~ carboxamide
/
OH 5-Chloro-N-((1-(2-((S)-2,3-
OH
CI dihydroxypropoxy)-4-(2-oxopyridin-
155 O N_N H 1(2H)-yl)phenyl)-5-iodo-lH-1,2,3-
triazol-4-yl)methyl)thiophene-2-
0
N
~ carboxamide
/
N N-((1-(2-(2-(1 H-Pyrazol-l-
N
ci yl)ethoxy)-4-(2-oxopyridin-1(2H)-
156 O NN=N _Z N yl)phenyl)-1H-1,2,3-triazol-4-
O yl)methyl)-5-chlorothiophene-2-
O
I N
carboxamide
Cs~ Ci 5-Chloro-N-((1-(4-(2-oxopiperidin-l-
N N=N H s~ yl)-2-thiomorpholinophenyl)-1H-
157 O ~ 1,2,3-triazol-4-yl)methyl)thiophene-
N O
2-carboxamide
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o0 5-Chloro-N-((1-(4-(2-oxopiperidin-l-
ci yl)-2-((l,l-
158 N N,S~N dioxo)thiomorpholino)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-
N o
2-carboxamide
o H
5-Chloro-N-((1-(2-(3-oxopiperazin-
s ci 1-yl)-4-(2-oxopiperidin-l-yl)phenyl)-
-yl)phenyl)-
N) NcN H ~
159 0 N 1H-1,2,3-triazol-4-
N o yl)methyl)thiophene-2-carboxamide
~ 5-Chloro-N-((1-(2-
o ci
N
N-N H (morpholinomethyl)-4-(2-
S ~
160 0 ~ NN oxopyridin-1(2H)-yl)phenyl)-1H-
N o 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
H ci 5-Chloro-N-((1-(2-((3-oxopiperazin-
o N N=N H s 1-yl)methyl)-4-(2-oxopyridin-1(2H)-
161 0 NN
yl)phenyl)-1 H- 1,2,3 -triazol-4-
0
N yl)methyl)thiophene-2-carboxamide
~ 5-Chloro-N-((1-(4-(2-oxopyridin-
s
N N-N H s ci 1(2H)-yl)-2-
162 0 N,,,N (thiomorpholinomethyl)phenyl)-1H-
N o 1,2,3-triazol-4-yl)methyl)thiophene-
~ 2-carboxamide
0 5-Chloro-N-((1-(4-(2-oxopyridin-
1%
o ci 1(2H)-yl)-2-(l,l,-
163 NN dioxothiomorpholinomethyl)phenyl)-
o
0 1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide
46
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ci 5-Chloro-N-((1-(2-ethoxy-4-(2-
--~'O ~~~ oxopyridin-1(2H)-yl)phenyl)-1H-
164 0 1,2,3-triazol-4-yl)methyl)thiophene-
N
2-carboxamide
N 5-Chloro-N-((1-(4-(2-oxopyridin-
ci 1(2H)-yl)-2-(pyridin-3-
165 0 N=N H s~ ylmethoxy)phenyl)-1H-1,2,3-triazol-
0
4-yl)methyl)thiophene-2-
o
N carboxamide
N N 5-Chloro-N-((1-(4-(2-oxopyridin-
i
ci 1(2H)-yl)-2-(N-(pyridine-3-
0 =N yl)pyridin-3-ylmethoxy)phenyl)-1H-
166 j:5._N%d%.__N
-Tr 1,2,3-triazol-4-yl)methyl)thiophene-
o
N
2-carboxamide
N 5-Chloro-N-((1-(4-(2-oxopyridin-
~
ci 1(2H)-yl)-2-(pyridin-4-
167 0 N=N H s ylmethoxy)phenyl)-1H-1,2,3-triazol-
0 NN 4-yl)methyl)thiophene-2-
o
N carboxamide
N 5-Chloro-N-((1-(4-(2-oxopyridin-
ci 1(2H)-yl)-2-(2-(pyridin-2-
168 0 N=N H s~ yl)ethoxy)phenyl)-1H-1,2,3-triazol-
0
4-yl)methyl)thiophene-2-
0
N carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
' N ci 1(2H)-yl)-2-(pyridin-2-
169 0 N=N H s~ ylmethoxy)phenyl)-1H-1,2,3-triazol-
0
4-yl)methyl)thiophene-2-
o
~ N carboxamide
47
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5-Chloro-N-((1-(4-(2-oxopyridin-
N 1(2H)-yl)-2-(quinolin-2-
ci ylmethoxy)phenyl)-1H-1,2,3-triazol-
170 O N=N H N S~
o N 4-yl)methyl)thiophene-2-
/ 0 carboxamide
I
5-Chloro-N-((1-(4-(2-oxopyridin-
-(4-(2-oxopyridin-
~
ci 1(2H)-yl)-2-(thiazol-4-
171 NQN-N N ~\ ylmethoxy)phenyl)-1H-1,2,3-triazol-
0 NJ 0
carboxamide
sN 5-Chloro-N-((1-(2-((2-methylthiazol-
ci 4-yl)methoxy)-4-(2-oxopyridin-
172 0 N=N H 5 \
N _~ N 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
/ p yl)methyl)thiophene-2-carboxamide
N
p N-((1-(2-((1H-Benzo[d]imidazol-2-
N ,% NH yl)methoxy)-4-(2-oxopyridin-1(2H)-
173 O N=N H ci yl)phenyl)-1H-1,2,3-triazol-4-
S~
o ~ niN ~ yl)methyl)-5-chlorothiophene-2-
N / 0 carboxamide
5-Chloro-N-((1-(4-(2-oxopyridin-
N= ci 1(2H)-yl)-2-(2-(pyridin-3-
174 0 N=N H s yl)ethoxy)phenyl)-1H-1,2,3-triazol-
0 I ~ NO~,,N
4-yl)methyl)thiophene-2-
/ o
~ N carboxamide
48
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N-((1-(2-((1,2,4-Oxadiazol-3-
N~N
ci yl)methoxy)-4-(2-oxopyridin-1(2H)-
175 o N~N=N N ~\ yl)phenyl)-1H-1,2,3-triazol-4-
o yl)methyl)-5-chlorothiophene-2-
i
N
carboxamide
/=\ 5-Chloro-N-((1-(2-((1-methyl-1 H-
N~N~,
ci imidazol-2-yl)methoxy)-4-(2-
176 ~ N _~ H oxopyridin-1(2H)-yl)phenyl)-1H-
o /~ 1,2,3-triazol-4-yl)methyl)thiophene-
~
N
2-carboxamide
N-((l -(2-((1 H-Imidazol-2-
N~NH
ci yl)methoxy)-4-(2-oxopyridin-1(2H)-
177 0 N yl)phenyl)-1H-1,2,3-triazol-4-
o yl)methyl)-5-chlorothiophene-2-
~
N
carboxamide
N-((1-(2-((l -((1 H-imidazol-2-
NN yl)methyl)-1H-imidazol-2-
N CI
H yl)methoxy)-4-(2-oxopyridin-1(2H)-
0 N-N H S ~
178 o N~~N yl)phenyl)-1H-1,2,3-triazol-4-
o yl)methyl)-5-chlorothiophene-2-
carboxamide
0 5-Chloro-N-((1-(2-((5-
N cl methylisoxazol-3-yl)methoxy)-4-(2-
179 0 N=N S oxopyridin-1(2H)-yl)phenyl)-1H-
O NN 1,2,3-triazol-4-yl)methyl)thiophene-
~ ~
N 2-carboxamide
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O\N N-((1-(2-(2-(1H-Pyrrol-l-yl)ethoxy)-
0 N_N s ci 4-(2-oxopyridin-1(2H)-yl)phenyl)-
0 180 NN 1H-1,2,3-triazol-4-yl)methyl)-5-
~
N (i 0 chlorothiophene-2-carboxamide
All the preferred, more preferred, and most preferred compounds listed above
are
selective inhibitors of Factor Xa.
Compositions
The present invention further provides compositions comprising one or more
compounds of Formula (I), (II), (Ia), or (Ib) or a pharmaceutically acceptable
salt, ester, or
prodrug thereof and a pharmaceutically acceptable carrier. It will be
appreciated that the
compounds of Formula (I), (II), (Ia), or (Ib) in this invention may be
derivatized at
functional groups to provide prodrug derivatives which are capable of
conversion back to
the parent compounds in vivo. Examples of such prodrugs include the
physiologically
acceptable and metabolically labile ester derivatives, such as methoxymethyl
esters,
methylthiomethyl esters, or pivaloyloxymethyl esters derived from a hydroxyl
group of the
compound or a carbamoyl moiety derived from an amino group of the compound.
Additionally, any physiologically acceptable equivalents of the compounds of
Formula (I),
(II), (Ia), or (Ib) similar to metabolically labile esters or carbamates,
which are capable of
producing the parent compounds of Formula (I), (II), (Ia), or (Ib) in vivo,
are within the
scope of this invention.
If pharmaceutically acceptable salts of the compounds of this invention are
utilized
in these compositions, those salts are preferably derived from inorganic or
organic acids and
bases. Included among such acid salts are the following: acetate, adipate,
alginate, aspartate,
benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor
sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,
fumarate,
lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate,
2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-
phenyl-
propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
tosylate and
undecanoate. Base salts include ammonium salts, alkali metal salts, such as
sodium and
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potassium salts, alkaline earth metal salts, such as calcium and magnesium
salts, salts with
organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and
salts with
amino acids such as arginine, lysine, and so forth.
Furthermore, the basic nitrogen-containing groups may be quaternized with
agents
like lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides,
bromides and
iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl
sulfates, long chain
halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; aralkyl
halides, such as benzyl and phenethyl bromides and others. Water or oil-
soluble or
dispersible products are thereby obtained.
The compounds utilized in the compositions and methods of this invention may
also
be modified by appending appropriate functionalities to enhance selective
biological
properties. Such modifications are known in the art and include those which
increase
biological penetration into a given biological system (e.g., blood, lymphatic
system, central
nervous system, etc.), increase oral availability, increase solubility to
allow administration
by injection, alter metabolism and alter rate of excretion.
The pharmaceutical compositions of the invention can be manufactured by
methods
well known in the art such as conventional granulating, mixing, dissolving,
encapsulating,
lyophilizing, or emulsifying processes, among others. Compositions may be
produced in
various forms, including granules, precipitates, or particulates, powders,
including freeze
dried, rotary dried or spray dried powders, amorphous powders, tablets,
capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or solutions.
Formulations may
optionally contain stabilizers, pH modifiers, surfactants, bioavailability
modifiers and
combinations of these.
Pharmaceutical formulations may be prepared as liquid suspensions or solutions
using a sterile liquid, such as oil, water, alcohol, and combinations thereof.
Pharmaceutically suitable surfactants, suspending agents or emulsifying
agents, may be
added for oral or parenteral administration. Suspensions may include oils,
such as peanut
oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension
preparation may also
contain esters of fatty acids, such as ethyl oleate, isopropyl myristate,
fatty acid glycerides
and acetylated fatty acid glycerides. Suspension formulations may include
alcohols, such as
ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
Ethers, such
51
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as poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil and
petrolatum, and
water may also be used in suspension formulations.
Pharmaceutically acceptable carriers that may be used in these compositions
include
ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as
human serum
albumin, buffer substances, such as phosphates, glycine, sorbic acid,
potassium sorbate,
partial glyceride mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-
based substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and
wool fat.
According to a preferred embodiment, the compositions of this invention are
formulated for pharmaceutical administration to a mammal, preferably a human
being.
Such pharmaceutical compositions of the invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally, buccally,
vaginally or via an
implanted reservoir. The term "parenteral" as used herein includes
subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial, intrastemal,
intrathecal,
intrahepatic, intralesional and intracranial injection or infusion techniques.
Preferably, the
compositions are administered orally or intravenously. The formulations of the
invention
may be designed as short-acting, fast-releasing, or long-acting. Still
further, compounds can
be administered in a local rather than systemic means, such as administration
(e.g.,
injection) as a sustained release formulation.
Sterile injectable forms of the compositions of this invention may be aqueous
or
oleaginous suspension. These suspensions may be formulated according to
techniques
known in the art using suitable dispersing or wetting agents and suspending
agents. The
sterile injectable preparation may also be a sterile injectable solution or
suspension in a non-
toxic parenterally acceptable diluent or solvent, for example as a solution in
1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are water,
Ringer's
solution and isotonic sodium chloride solution. In addition, sterile, fixed
oils are
conventionally employed as a solvent or suspending medium. For this purpose,
any bland
fixed oil may be employed including synthetic mono- or di-glycerides. Fatty
acids, such as
oleic acid and its glyceride derivatives are useful in the preparation of
injectables, as are
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natural pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their
polyoxyethylated versions. These oil solutions or suspensions may also contain
a long-
chain alcohol diluent or dispersant, such as carboxymethyl cellulose or
similar dispersing
agents which are commonly used in the formulation of pharmaceutically
acceptable dosage
forms including emulsions and suspensions. Other commonly used surfactants,
such as
Tweens, Spans and other emulsifying agents or bioavailability enhancers which
are
commonly used in the manufacture of pharmaceutically acceptable solid, liquid,
or other
dosage forms may also be used for the purposes of formulation. Compounds may
be
formulated for parenteral administration by injection such as by bolus
injection or
continuous infusion. A unit dosage form for injection may be in ampoules or in
multi- dose
containers.
The pharmaceutical compositions of this invention may be in any orally
acceptable
dosage form, including capsules, tablets, aqueous suspensions or solutions. In
the case of
tablets for oral use, carriers that are commonly used include lactose and corn
starch.
Lubricating agents, such as magnesium stearate, are also typically added. For
a capsule
form, useful diluents include lactose and dried cornstarch. When aqueous
suspensions are
required for oral use, the active ingredient is combined with emulsifying and
suspending
agents. If desired, certain sweetening, flavoring or coloring agents may also
be added.
Alternatively, the pharmaceutical compositions of this invention may be in the
form
of suppositories for rectal administration. These may be prepared by mixing
the agent with
a suitable non-irritating excipient which is solid at room temperature but
liquid at rectal
temperature and therefore will melt in the rectum to release the drug. Such
materials
include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be in a topical
form,
especially when the target of treatment includes areas or organs readily
accessible by topical
application, including diseases of the eye, the skin, or the lower intestinal
tract. Suitable
topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract may be effected in a rectal
suppository formulation (see above) or in a suitable enema formulation.
Topically-
transdermal patches may also be used. For topical applications, the
pharmaceutical
compositions may be formulated in a suitable ointment containing the active
component
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suspended or dissolved in one or more carriers. Carriers for topical
administration of the
compounds of this invention include, but are not limited to, mineral oil,
liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene
compound,
emulsifying wax and water. Alternatively, the pharmaceutical compositions may
be
formulated in a suitable lotion or cream containing the active components
suspended or
dissolved in one or more pharmaceutically acceptable carriers. Suitable
carriers include
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, wax, cetyl
alcohol,
2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as
micronized suspensions in isotonic, pH adjusted sterile saline, or,
preferably, as solutions in
isotonic, pH adjusted sterile saline, either with our without a preservative,
such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical
compositions may be formulated in an ointment, such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by
nasal aerosol or inhalation. Such compositions are prepared according to
techniques known
in the art of pharmaceutical formulation and may be prepared as solutions in
saline,
employing benzyl alcohol or other suitable preservatives, absorption promoters
to enhance
bioavailability, fluorocarbons and/or other conventional solubilizing or
dispersing agents.
Any of the above dosage forms containing effective amounts are within the
bounds
of routine experimentation and within the scope of the invention. A
therapeutically
effective dose may vary depending upon the route of administration and dosage
form. The
preferred compound or compounds of the invention is a formulation that
exhibits a high
therapeutic index. The therapeutic index is the dose ratio between toxic and
therapeutic
effects which can be expressed as the ratio between LD50 and ED50. The LD50 is
the dose
lethal to 50 % of the population and the ED50 is the dose therapeutically
effective in 50% of
the population. The LD50 and ED50 are determined by standard pharmaceutical
procedures
in animal cell cultures or experimental animals. Effective doses can be
extrapolated from
dose-response curves derived from in vitro or animal model test systems. For
example, an
effective dose will typically be in the range of about 0.00 1 to about 1000 mg
per kilogram
body weight of the recipient per day ("mg/kg/day"), preferably about 0.01 to
about 100
mg/kg/day, and more preferably about 0.1 to about 10 mg/kg/day.
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The amount of the compound in a formulation can vary within the full range
employed by those skilled in the art. Typically, the formulation will contain,
on a weight
percent (wt%) basis, from about 0.01-99.99 wt% of a compound of the present
invention
based on the total formulation, with the balance being one or more suitable
pharmaceutical
excipients. Preferably, the compound is present at a level of about 1-90 wt%
or about 20-80
wt%.
Besides those representative dosage forms described above, pharmaceutically
acceptable excipients and carriers and dosage forms are generally known to
those skilled in
the art and are included in the invention. It should be understood that a
specific dosage and
treatment regimen for any particular patient will depend upon a variety of
factors, including
the activity of the specific compound employed, the age, body weight, general
health, sex
and diet of the patient, and the time of administration, rate of excretion,
drug combination,
judgment of the treating physician and severity of the particular disease
being treated. The
amount of active ingredient(s) will also depend upon the particular compound
and other
therapeutic agent, if present, in the composition.
Methods of Use
The invention provides methods of inhibiting or decreasing Factor Xa activity
as
well as treating or ameliorating a Factor Xa associated state, symptom,
disorder or disease
in a patient in need thereof (e.g., human or non-human). "Treating" within the
context of
the invention means an alleviation of symptoms associated with a disorder or
disease, or
halt of further progression or worsening of those symptoms, or prevention or
prophylaxis of
the disease or disorder.
The term "mammal" includes organisms which express Factor Xa. Examples of
mammals include mice, rats, cows, sheep, pigs, goats, horses, bears, monkeys,
dogs, cats
and, preferably, humans. Transgenic organisms which express Factor Xa are also
included
in this definition.
The inventive methods comprise administering an effective amount of a compound
or composition described herein to a mammal or non-human animal. As used
herein,
"effective amount" of a compound or composition of the invention includes
those amounts
that antagonize or inhibit Factor Xa. An amount which antagonizes or inhibits
Factor Xa is
detectable, for example, by any assay capable of determining Factor Xa
activity, including
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the one described below as an illustrative testing method. Effective amounts
may also
include those amounts which alleviate symptoms of a Factor Xa associated
disorder
treatable by inhibiting Factor Xa. Accordingly, "antagonists of Factor Xa"
include
compounds which interact with the Factor Xa and modulate, e.g., inhibit or
decrease, the
ability of a second compound, e.g., another Factor Xa ligand, to interact with
the Factor Xa.
The Factor Xa binding compounds are preferably antagonists of Factor Xa. The
language
"Factor Xa binding compound" (e.g., exhibits binding affinity to the receptor)
includes
those compounds which interact with Factor Xa resulting in modulation of the
activity of
Factor Xa. Factor Xa binding compounds may be identified using an in vitro
(e.g., cell and
non-cell based) or in vivo method. A description of an in vitro method is
provided below.
The amount of compound present in the methods and compositions described
herein
should be sufficient to cause a detectable decrease in the severity of the
disorder, as
measured by any of the assays described in the examples. The amount of Factor
Xa
modulator needed will depend on the effectiveness of the modulator for the
given cell type
and the length of time required to treat the disorder. The effective amount is
generally an
amount described herein above. In certain embodiments, the compositions of
this invention
may further comprise another therapeutic agent. When a second agent is used,
the second
agent may be administered either as a separate dosage form or as part of a
single dosage
form with the compounds or compositions of this invention. While one or more
of the
inventive compounds can be used in an application of monotherapy to treat a
disorder,
disease or symptom, they also may be used in combination therapy, in which the
use of an
inventive compound or composition (therapeutic agent) is combined with the use
of one or
more other therapeutic agents for treating the same and/or other types of
disorders,
symptoms and diseases. Combination therapy includes administration of the two
or more
therapeutic agents concurrently or sequentially. The agents may be
administered in any
order. Alternatively, the multiple therapeutic agents can be combined into a
single
composition that can be administered to the patient. For instance, a single
pharmaceutical
composition could comprise the compound or pharmaceutically acceptable salt or
solvate
according to the any one of Formulas (I), (II), (Ia) and (Ib), another
therapeutic agent (e.g.,
methotrexate) or a pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable excipient or carrier.
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The invention comprises a compound having any one of Formulas (I), (II), (Ia)
and
(Ib), a method for making an inventive compound, a method for making a
pharmaceutical
composition from at least one inventive compound and at least one
pharmaceutically
acceptable carrier or excipient, and a method of using one or more inventive
compounds to
treat a variety of disorders, symptoms and diseases (e.g., inflammatory,
autoimmune,
neurological, neurodegenerative, oncology and cardiovascular), such as RA,
osteoarthritis,
irritable bowel disease IBD, asthma, chronic obstructive pulmonary disease
COPD and MS.
The inventive compounds and their pharmaceutically acceptable salts and/or
neutral
compositions may be formulated together with a pharmaceutically acceptable
excipient or
carrier and the resulting composition may be administered in vivo to mammals,
such as
men, women and animals, to treat a variety of disorders, symptoms and
diseases.
Furthermore, the inventive compounds can be used to prepare a medicament that
is useful
for treating a variety of disorders, symptoms and diseases.
Kits
Still another aspect of this invention is to provide a kit comprising separate
containers in a single package, wherein the inventive pharmaceutical
compounds,
compositions and/or salts thereof are used in combination with
pharmaceutically acceptable
carriers to treat states, disorders, symptoms and diseases where Factor Xa
plays a role.
General methods
The starting materials and reagents used in preparing these compounds
generally are
either available from commercial suppliers, such as Aldrich Chemical Co., or
are prepared
by methods known to those skilled in the art following procedures set forth in
references
such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New
York,
1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier
Science
Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley
& Sons:
New York, 2005, Volumes 1-65. The following synthetic reaction schemes are
merely
illustrative of some methods by which the compounds of the present invention
can be
synthesized, and various modifications to these synthetic reaction schemes can
be made and
will be suggested to one skilled in the art having referred to the disclosure
contained in this
application.
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The starting materials and the intermediates of the synthetic reaction schemes
can be
isolated and purified if desired using conventional techniques, including but
not limited to,
filtration, distillation, crystallization, chromatography, and the like. Such
materials can be
characterized using conventional means, including physical constants and
spectral data.
Unless specified to the contrary, the reactions described herein preferably
are
conducted under an inert atmosphere at atmospheric pressure at a reaction
temperature
range of from about -78 C to about 150 C, more preferably from about 0 C to
about 125
C, and most preferably and conveniently at about room (or ambient)
temperature, e.g.,
about 20 C to about 75 C.
Referring to the examples that follow, compounds of the present invention were
synthesized using the methods described herein, or other methods, which are
well known in
the art.
The compounds and/or intermediates may be characterized by high performance
liquid chromatography (HPLC) using a Waters Alliance chromatography system
with a
2695 Separation Module (Milford, Mass.). The analytical columns may be C-18
SpeedROD
RP-18E Columns from Merck KGaA (Darmstadt, Germany). Alternately,
characterization
may be performed using a Waters Unity (UPLC) system with Waters Acquity UPLC
BEH
C-18 2.1 mm x 15 mm columns. A gradient elution may be used, typically
starting with 5
% acetonitrile/95 % water and progressing to 95 % acetonitrile over a period
of 5 minutes
for the Alliance system and 1 minute for the Acquity system. All solvents may
contain 0.1
% trifluoroacetic acid (TFA). Compounds may be detected by ultraviolet light
(UV)
absorption at either 220 or 254 nm. HPLC solvents may be from EMD Chemicals,
Inc.
(Gibbstown, NJ). In some instances, purity may be assessed by thin layer
chromatography
(TLC) using glass backed silica gel plates, such as, for example, EMD Silica
Ge160 2.5 cm
x 7.5 cm plates. TLC results may be readily detected visually under
ultraviolet light, or by
employing well known iodine vapor and other various staining techniques.
Mass spectrometric analysis may be performed on one of two Agilent 1100 series
LCMS instruments with acetonitrile / water as the mobile phase. One system
using TFA as
the modifier and measures in positive ion mode (reported as MH+, (M+1) or
(M+H)+) and
the other may use either formic acid or ammonium acetate and measures in both
positive
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(reported as MH+, (M+1) or (M+H)+) and negative (reported as M-, (M-1) or (M-
H)-) ion
modes.
Nuclear magnetic resonance (NMR) analysis may be performed on some of the
compounds with a Varian 400 MHz NMR (Palo Alto, Calif.). The spectral
reference may be
either TMS or the known chemical shift of the solvent.
The purity of some of compounds of the invention may be assessed by elemental
analysis (Robertson Microlit, Madison NJ.).
Melting points may be determined on a Laboratory Devices Mel-Temp apparatus
(Holliston, Mass.).
Preparative separations may be carried out using either an Sql6x or an Sgl00c
chromatography system and prepackaged silica gel columns all purchased from
Teledyne
Isco, (Lincoln, NE). Alternately, compounds and intermediates may be purified
by flash
column chromatography using silica gel (230-400 mesh) packing material, or by
HPLC
using a C- 18 reversed phase column. Typical solvents employed for the Isco
systems and
flash column chromatography may be dichloromethane, methanol, ethyl acetate,
hexane,
acetone, aqueous hydroxyamine and triethyl amine. Typical solvents employed
for the
reverse phase HPLC may be varying concentrations of acetonitrile and water
with 0.1 %
trifluoroacetic acid.
EXAMPLES
The following abbreviations are used throughout the Examples:
L = microliter
M = micromolar
AIBN = azobisisobutyronitrile
aq. = aqueous
Boc = tert-butoxycarbonyl
BOP = benzotriazol-l-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate
conc. = concentrated
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM = dichloromethane
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DIEA = diisopropylethyl amine
DMF = dimethyl formamide
DMSO = dimethyl sulfoxide
eq. = equivalent
EtOAc = ethyl acetate
g = gram
h or hr(s) = hour(s)
HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate
HOBt = N-hydroxybenzotriazole
HPLC = high pressure liquid chromatography
IC50 = the concentration of an inhibitor that is required for 50 % inhibition
of an
enzyme in vitro
kg = kilogram
M = molar
m/z = mass to charge ratio
MeOH = methanol
mg = milligram
MHz = mega Hertz
min = minute
mL = milliliter
mM = millimolar
mm = millimeter
mmol = millimole
mOD/min = millioptical density units per minute
MS = Mass Spec
N = Normal
NaSMe = sodium methylthiolate
NBS = N-bromosuccinamide
nBuOH = n-butanol
ng = nanogram
nM = nanomolar
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nm = nanometer
Pd(PPh3)4 = tetrakis-(triphenylphosphine)-palladium
PEG = polyethylene glycol
pM = picomolar
PPh3 or Ph3P = triphenyl phosphine
PyBOP = (benzotriazol-l-yloxy)tripyrrolidinophosphonium Hexafluorophosphate
prep = preparative
Ra-Ni = Rainey Nickel
RT = room temperature
TEA = triethylamine
TFA = trifluoroacetic acid
TMSC1 = trimethylsilyl chloride
TLC = thin layer chromatography
EXAMPLE 1
5-Chloro-N-((1-(2-(methylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (1)
ci
HN N-N H S
U
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SCHEME 1
F F
X5/NH2 CI
I / F N-N H
1.1 1.2 NN
CI
HO S CI \~N 6 1.5
~ /
O
1.3 1.4
CI CI
F N-N H HN'O' N-N H S
~ O I\ N~N O I\ NN \
N ~
/ 0 N / O
I I
1.6 1.7
Step 1:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and
stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small
portions. The
resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g,
28.8 mmol) was
dissolved in 10 mL water and chilled in ice bath. This cold solution was then
added to the
TFA solution in three portions. The mixture was stirred in ice bath for 1 hr
and
concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and
washed with water three times. The organic phase was dried using MgS04 and
concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a
brownish waxy
solid in > 99 % yield.
In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol)
was
dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously
stirred
solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise.
The
resulting solution was stirred for 3 hrs at RT and then concentrated in vacuo.
The residue
was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution
was
added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT
overnight during which time solid precipitated out. 600 mL hexane was added
and the
mixture was vigorously stirred for a few hours. The solid was collected by
filtration and
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washed with hexane to give the product 1.4 (9.47 g, 85 %) which was used
directly without
further purification. MS found for CgH6C1NOS as (M+H)+ 200.0, 202.0 (Cl
pattern).
Step 2:
To a solution of the aryl azide 1.2 (27 mmol) and alkyne 1.4 (5.37 g, 27 mmol)
in
500 mL dry methanol, were added DBU (4.00 mL, 54 mmol) and Cul (5.13 g, 27
mmol).
The mixture was stirred at RT overnight. The mixture was then diluted with
1.01iter
acetonitrile and stirred vigorously for 1 hr. It was filtered through celite
and the filtrate was
concentrated and purified using flash column to give compound 1.5 (8.30 g, 67
%). MS
found for compound 1.5 C14H9C1FIN4OS as (M+H)+ 463.0, 465.0 (Cl pattern).
Step 3:
To a solution of aryl iodide 1.5 (100 mg, 0.22 mmol) and 2-hydroxypyridine (42
mg,
0.44 mmol) in 5 mL dry DMSO in a sealed tube, were added 8-hydroxyquinoline
(10 mg,
0.007 mmol), Cul (13 mg, 0.07 mmol) and Cs2CO3 (145 mg, 0.44 mmol). The
mixture was
stirred in 120 C bath overnight. It was then filtered and the filtrate was
directly subjected
to reverse phase preparative HPLC to isolate compound 1.6 (66 mg) as a white
powder in
68 % yield after lyophilization. MS found for C19H13C1FN502S as (M+H)+ 430.0,
432.0
(Cl pattern).
Step 4:
To a solution of compound 1.6 (66 mg, 0.15 mmol) in 1 mL anhydrous DMSO in a
sealed tube, was added methylamine (2.0 M in THF, 4 mL, 8.0 mmol). The mixture
was
stirred in 125 C bath overnight. It was cooled to RT, concentrated in vacuo
and directly
subjected to reverse phase HPLC to isolate the title compound as a white
powder after
lyophilization. MS found for C2oHi7C1N602S (M+H)+ 441.1, 443.1 (Cl pattern).
EXAMPLE 2
5-Chloro-N-((1-(2-(dimethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (2)
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CI
N. N N-N H S ~
N \
O I ~ Nv `~ O
/
N
To a solution of compound 1.6 (55 mg, 0.13 mmol) in 2 mL anhydrous DMSO in a
sealed tube, was added dimethylamine (2.0 M in MeOH, 2 mL, 4.0 mmol). The
mixture
was stirred in 125 C bath overnight. It was cooled to RT, concentrated in
vacuo and
directly subjected to reverse phase HPLC to isolate the title compound as a
white powder
after lyophilization. MS found for C21H19C1N602S (M+H)+ 455.1, 457.1 (Cl
pattern).
EXAMPLE 3
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyrrolidin-1-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (3)
CI
N N-N H
N
O I O
N
To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL anhydrous DMSO in a
sealed tube was added 1 mL pyrrolidine. The mixture was stirred at 140 C
overnight. It
was cooled to RT, concentrated in vacuo and directly subjected to reverse
phase HPLC to
isolate the title compound as a white powder after lyophilization. MS found
for
C23H21C1N602S (M+H)+ 481.1, 483.1 (Cl pattern).
EXAMPLE 4
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperidin-1-yl)phenyl)-1 H-1,2,3 -
triazol-4-
yl)methyl)thiophene-2-carboxamide (4)
ON CI
N-N H S ~
O I ~ Nv N
N O
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To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL anhydrous DMSO in a
sealed tube, was added 1 mL piperidine. The mixture was stirred at 140 C
overnight. It
was cooled to RT, concentrated in vacuo and directly subjected to reverse
phase HPLC to
isolate the title compound as a white powder after lyophilization. MS found
for
C24H23C1N602S (M+H)+ 495.1, 497.1 (Cl pattern).
EXAMPLE 5
5-Chloro-N-((1-(2-morpholino-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -
triazol-4-
yl)methyl)thiophene-2-carboxamide (5)
(N) CI
I~N H S ~
N \
O I ~ Nv `~ O
/
I N
To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL anhydrous DMSO in a
sealed tube, was added 1 mL morpholine. The mixture was stirred in 140 C bath
overnight.
It was cooled to RT, concentrated in vacuo and directly subjected to reverse
phase HPLC to
isolate the title compound as a white powder after lyophilization. MS found
for
C23H21C1N603S (M+H)+ 497.1, 499.1 (Cl pattern).
EXAMPLE 6
5-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (6)
H
N
CI
N N-N H S ~
Nv `~N \
O I ~ O
/
N
To a solution of compound 1.6 (100 mg, 0.23 mmol) in 2 mL anhydrous DMSO in a
sealed tube was added 2-oxopiperazine (1.15 g, 11.5 mmol). The mixture was
stirred in
140 C bath for overnight. It was cooled to RT, and directly subjected to
reverse phase
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HPLC to isolate the title compound as a white powder after lyophilization. MS
found for
C23H2OC1N703S (M+H)+ 510.1, 512.1.
EXAMPLE 7
5-Chloro-N-((1-(2-(4-methyl-3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (7)
1
O~N`
NJl N-N H S CI
O I ~ Nv N
/ O
N
The title compound was prepared by a similar procedure as described in Example
6.
MS found for C24H22C1N703S (M+H)+ 524.1, 526.1 (Cl pattern).
EXAMPLE 8
5-Chloro-N-((1-(2-(4-ethyl-3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (8)
r
N) N-N S ci
N~~ N ~
0 I ~ O
/
I N
The title compound was prepared by a similar procedure as described in Example
7.
MS found for C25H24C1N703S (M+H)+ 538.1, 540.1 (Cl pattern).
EXAMPLE 9
5-Chloro-N-((1-(2-(4-isopropyl-3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (9)
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Y
ON
T `
NJl N-N H CI
S ~
O I Nv`~N \
N / O
The title compound was prepared by a similar procedure as described in Example
7.
MS found for C26H26C1N703S (M+H)+ 552.1, 554.1 (Cl pattern).
EXAMPLE 10
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (10)
S1 CI
NJ N-N H S ~
Nv`~N \
O I O
/
I N
To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL anhydrous DMSO in a
sealed tube was added 1 mL thiomorpholine. The mixture was stirred in 140 C
bath for
overnight. It was cooled to RT, concentrated in vacuo and directly subjected
to reverse
phase HPLC to isolate the title compound as a white powder after
lyophilization. MS found
for C23H21C1N602S2 (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 11
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((1-oxo-)thiomorpholino)phenyl)-1
H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (11)
O
i
CS
N CI
O N~ N S ~
~
N I O
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To a solution of 5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-
thiomorpholinophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (19
mg,
0.037 mmol, prepared as shown in Example 10) in 8 mL methanol and 4 mL water
was
added oxone (23 mg, 0.037 mmol). The mixture was stirred at RT for 10 min and
directly
subjected to reverse phase HPLC to isolate the title compound as a white
powder after
lyophilization. MS found for C23H21C1N603S2 (M+H)+ 529.1, 531.1 (Cl pattern).
EXAMPLE 12
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((1,1-dioxo-
)thiomorpholino)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (12)
.,0
CI
N N-N H
O I Nv N
O
N
To a solution of 5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-
thiomorpholinophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (19
mg,
0.037 mmol, prepared as shown in Example 10) in 6 mL methanol and 3 mL water
was
added oxone (192 mg, 0.31 mmol). The mixture was stirred at RT for 1 hr and
directly
subjected to reverse phase HPLC to isolate the title compound as a white
powder after
lyophilization. MS found for C23H21C1N604S2 (M+H)+ 545.1, 547.1 (Cl pattern).
EXAMPLE 13
N-((1-(2-(4-Acetylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (13)
O)"00-
N CI
NJ N-N H S ~
Nv`~ N \
O I ~ O
/
N
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5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-l-yl)phenyl)-1 H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (15 mg, 0.003 mmol, prepared using
a
procedure similar to that described in Example 1) was dissolved in 1.5 mL
anhydrous
DMSO. To it was added 80 L pyridine and 60 L acetyl chloride. The mixture
was stirred
at RT for overnight and directly subjected to reverse phase HPLC to isolate
the title
compound as a white powder after lyophilization. MS found for C25H24C1N703S
(M+H)+
538.1, 540.1 (Cl pattern).
EXAMPLE 14
5-Chloro-N-((1-(2-(4-(1-iminoethyl)piperazin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (14)
HN,~r
CNl CI
NJ N-N H N S ~
O I ~ Nv N \
/ O
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1 H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (15 mg, 0.003 mmol) was dissolved
in 2 mL
anhydrous methanol. To it was added 27 L DIEA (0.15 mmol) and 20 mg ethyl
acetimidate hrdrochloride (0.15 mmol). The mixture was stirred in 100 C in a
sealed tube
for overnight and directly subjected to reverse phase HPLC to isolate the
title compound as
a white powder after lyophilization. MS found for C25H25C1N802S (M+H)+ 537.1,
539.1
(Cl pattern).
EXAMPLE 15
4-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)piperazine-l-carboxamide (15)
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OyNHZ
N CI
NJ N-N H S ~
Nv`~N \
O I O
N
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-l-yl)phenyl)-1 H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (50 mg, 0.1 mmol) was dissolved in
3 mL
water and 0.5 mL DMSO. To it was added KOCN (41 mg, 0.5 mmol). The mixture was
stirred at RT for 2 days and directly subjected to reverse phase HPLC to
isolate the title
compound as a white powder after lyophilization. MS found for C24H23C1N803S
(M+H)+
539.1, 541.1 (Cl pattern).
EXAMPLE 16
5-Chloro-N-((1-(2-(4-(dimethylamino)piperidin-l-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (16)
N
6 CI
N N=N H S ~
N~, N ~
0 I ~ O
/
I N
The title compound was prepared by a similar procedure as described in Example
5.
MS found for C26H28C1N7O2S (M+H)+ 538.1, 540.1 (Cl pattern).
EXAMPLE 17
N-((1-(2-(4-Aminopiperidin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (17)
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NH2
CI
N N-N H S ~
O I ~ Nv `~N \
/ O
I N
Compound 1.6 (200 mg, 0.47 mmol) was dissolved in 4 mL anhydrous DMSO in a
sealed tube. 4-N-Boc-aminopyridine (2.82 g, 14.1 mmol) was added. The mixture
was
stirred in 120 C bath for 24 hrs. It was cooled and diluted with 200 mL ethyl
acetate. It was
washed with brine three times, dried and concentrated in vacuo. The residue
was then
treated with 10 mL DCM and 10 mL TFA at RT for 1 hr. The mixture was then
concentrated in vacuo and purified by reverse phase preparative HPLC to
isolate the title
compound. MS found for C24H24C1N702S (M+H)+ 510.1, 512.1 (Cl pattern).
EXAMPLE 18
N-((1-(2-(4-Acetamidopiperidin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (18)
O
HN'k
6 CI
N N-N H
O I ~ Nv N
O
I N
The title compound was prepared from N-((1-(2-(4-aminopiperidin-l-yl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-
carboxamide by a similar procedure as described in Example 13. MS found for
C26H26C1N703S (M+H)+ 552.1, 554.1 (Cl pattern).
EXAMPLE 19
N-((1-(2-(4-Acetamidinopiperidin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (19)
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NH
HNfl'%"
6 CI
N N-N H S ~
O I ~ Nv N \
O
I N
The title compound was prepared from N-((1-(2-(4-aminopiperidin-l-yl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-
carboxamide by a similar procedure as described in Example 14. MS found for
C26H27C1N802S (M+H)+ 551.1, 553.1 (Cl pattern).
EXAMPLE 20
1-(1-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5-
(2-
oxopyridin-1(2H)-yl)phenyl)piperidin-4-yl)urea (20)
0
HNNH2
6 CI
N N-N H
N
O I O
N
The title compound was prepared from N-((l-(2-(4-aminopiperidin-l-yl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-
carboxamide by a similar procedure as described in Example 15. MS found for
C25H25C1N803S (M+H)+ 553.1, 555.1 (Cl pattern).
EXAMPLE 21
5-Chloro-N-((1-(2-(4-hydroxypiperidin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (21)
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OH
CI
6N N-N H S
O I \ N~N ~
N ~
/ O
Compound 1.6 (100 mg, 0.23 mmol) was dissolved in 2 mL anhydrous DMSO in a
sealed tube. 4-Hydroxypiperidine (0.95 g, 9.3 mmol) was added. The mixture was
stirred in
130 C bath for 16 hrs. The mixture was directly subjected to reverse phase
preparative
HPLC to isolated the title compound. MS found for C24H23C1N603S (M+H)+ 511.1,
513.1
(Cl pattern).
EXAMPLE 22
5-Chloro-N-((1-(2-((R)-3 -hydroxypiperidin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (22)
yOH
H CI
N N_ N
O S
~
I\
N ~
/ O
I
To a solution of (R)-3-hydoxypiperidine hydrochloride (762 mg, 5.6 mmol) in 2
mL
anhydrous DMSO in a sealable tube was added sodium hydride (60 % in mineral
oil, 224
mg, 5.6 mmol). The mixture was stirred at RT for 30 min before compound 1.6
(80 mg,
0.18 mmol) was added. The tube was then sealed and stirred in 125 C bath for
18 hrs. The
mixture was directly subjected to reverse phase preparative HPLC to isolated
the title
compound. MS found for C24H23C1N603S (M+H)+ 511.1, 513.1 (Cl pattern).
EXAMPLE 23
5-Chloro-N-((1-(2-((S)-3-hydroxypiperidin-1-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (23)
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H
(OH CI
N N-N H S ~
O I ~ Nv `~N \
/ O
I N
To a solution of (S)-3-hydoxypiperidine hydrochloride (762 mg, 5.6 mmol) in 2
mL
anhydrous DMSO in a sealable tube was added sodium hydride (60 % in mineral
oil, 224
mg, 5.6 mmol). The mixture was stirred at RT for 30 min before compound 1.6
(80 mg,
0.18 mmol) was added. The tube was then sealed and the mixture was stirred in
125 C
bath for 18 hrs. The mixture was directly subjected to reverse phase
preparative HPLC to
isolated the title compound. MS found for C24H23C1N603S (M+H)+ 511.1, 513.1
(Cl
pattern).
EXAMPLE 24
1-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)piperidine-4-carboxylic acid (24)
CO2H
CI
N N-N H S ~
Nv N \
O I ~ O
/
N
To a solution of compound 1.6 (200 mg, 0.47 mmol) in 2 mL anhydrous DMSO in a
sealed tube was added 2 mL methyl isonipecotate. The mixture was heated in 140
C bath
for 20 hrs and concentrated in vacuo. The residue was then dissolved in 20 mL
methanol.
To it were added 10 mL water and 100 mg lithium hydroxide hydrate. The mixture
was
stirred at RT for 4 hrs and concentrated in vacuo. The residue was directly
subjected to
reverse phase preparative HPLC to isolated the title compound. MS found for
C25H23C1N604S (M+H)+ 539.1, 541.1 (Cl pattern).
EXAMPLE 25
1-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)piperidine-4-carboxamide (25)
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O NHZ
CI
N N-N H
Nv`~N
O I O
/
N
To a solution of compound 1.6 (100 mg, 0.23 mmol) in 2 mL anhydrous DMSO in a
sealed tube was added 1.0 g isonipecotamide (7.75 mmol). The mixture was
heated in 140
C bath for 20 hrs and directly subjected to reverse phase preparative HPLC to
isolated the
title compound. MS found for C25H24C1N703S (M+H)+ 538.1, 540.1 (Cl pattern).
EXAMPLE 26
5-Chloro-N-((1-(2-(2-hydroxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2, 3-
triazol-4-yl)methyl)thiophene-2-carboxamide (26)
OH
CI
NH N=N H S
O I Nv N \
I N ~
/ O
To a solution of compound 1.6 (65 mg, 0.15 mmol) in 1 mL anhydrous DMSO in a
sealed tube was added 1 mL ethanolamine. The mixture was heated in 125 C bath
for 18
hrs and directly subjected to reverse phase preparative HPLC to isolated the
title compound.
MS found for C21H19C1N603S (M+H)+ 471.1, 473.1 (Cl pattern).
EXAMPLE 27
5-Chloro-N-((1-(2-(2-methoxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (27)
o" cl
NH N=N H S ~
O `~
I Nv N \
O
I N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C22H21C1N603S (M+H)+ 485.1, 487.1 (Cl pattern).
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EXAMPLE 28
5-Chloro-N-((1-(2-((2-hydroxyethyl)(methyl)amino)-4-(2-oxopyridin-l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (28)
OH
CI
N/ N / N S ~
~
O I\ O
/
I N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C22H21C1N603S (M+H)+ 485.1, 487.1 (Cl pattern).
EXAMPLE 29
5-Chloro-N-((1-(2-((2-methoxyethyl)(methyl)amino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (29)
ON.
CI
N/ N=N H
N
O
N / O
The title compound was prepared a similar procedure as described in Example
26.
MS found for C23H23C1N603S (M+H)+ 499.1, 501.1 (Cl pattern).
EXAMPLE 30
N-((1-(2-(2-Aminoethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (30)
CI
NH
NH N-N H S ~
N ~
O I
N O
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The title compound was prepared by a similar procedure as described in Example
26. MS found for C21H20C1N702S (M+H)+ 470.1, 472.1 (Cl pattern).
EXAMPLE 31
-Chloro-N-((1-(2-(2-(dimethylamino)ethylamino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
5 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (31)
N
CI
NH N-N H S ~
O I Nv N \
/ O
I N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C23H24C1N702S (M+H)+ 498.1, 500.1 (Cl pattern).
EXAMPLE 32
5-Chloro-N-((1-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-(2-oxopyridin-
1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (32)
N
CI
NØ1 N-N H S ~
O Nv `~N
N O
The title compound was prepared by a similar procedure as described in Example
26. MS found for C24H26C1N702S (M+H)+ 512.1, 514.1 (Cl pattern).
EXAMPLE 33
5-Chloro-N-((1-(2-(3-hydroxypropylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (33)
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CoH ci
NH N-N H S \1
N
O
O
The title compound was prepared by a similar procedure as described in Example
26. MS found for C22H21C1N603S (M+H)+ 485.1, 487.1 (Cl pattern).
EXAMPLE 34
5-Chloro-N-((1-(2-(3-methoxypropylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (34)
c e ci
NH N-N H S ~
O j(t Nv `~N \
O
N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C23H23C1N603S (M+H)+ 499.1, 501.1 (Cl pattern).
EXAMPLE 35
5-Chloro-N-((1-(2-((3-hydroxypropyl)(methyl)amino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (35)
OH CI
N~ N-N H S
O
O
N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C23H23C1N603S (M+H)+ 499.1, 501.1 (Cl pattern).
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EXAMPLE 36
5-Chloro-N-((1-(2-((3-methoxypropyl)(methyl)amino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (36)
CO'C1000, CI
N-N H S \
NO
O I Nv `~N N.
/
N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C24H25C1N603S (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 37
N-((1-(2-(3-Aminopropylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (37)
c NH2 ci
NH N-N H S ~
O I NN
N ~
/ O
I
The title compound was prepared by a similar procedure as described in Example
26. MS found for C22H22C1N702S (M+H)+ 484.1, 486.1 (Cl pattern).
EXAMPLE 38
5 -Chloro-N-((1-(2-(3-(dimethylamino)propylamino)-4-(2-oxopyridin- l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (38)
N I ci
NH N-N H S ~
O Nv,N \
O
I N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C24H26C1N702S (M+H)+ 512.1, 514.1 (Cl pattern).
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EXAMPLE 39
5-Chloro-N-((1-(2-((3-(dimethylamino)propyl)(methyl)amino)-4-(2-oxopyridin-
1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (39)
N."
CI
eNN-N H S ~
O Nv `~N \
O
N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C25H28C1N702S (M+H)+ 526.1, 528.1 (Cl pattern).
EXAMPLE 40
5-Chloro-N-((1-(2-(methyl(3-(methylamino)propyl)amino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (40)
NH
CI
eN #, N-N H S ~
O I Nv `~N \
N / O
The title compound was prepared by a similar procedure as described in Example
26. MS found for C24H26C1N702S (M+H)+ 512.1, 514.1 (Cl pattern).
EXAMPLE 41
5-Chloro-N-((1-(2-(methyl(2-(methylamino)ethyl)amino)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (41)
H
N~
CI
N N-N H S ~
Nv,N \
O I O
N
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The title compound was prepared by a similar procedure as described in Example
26. MS found for C23H24C1N702S (M+H)+ 498.1, 500.1 (Cl pattern).
EXAMPLE 42
N-((1-(2-(1 H-Imidazol-l-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (42)
j~ CI
N N-N H
O ~ Nv N
O
I N
The title compound was prepared by a similar procedure as described in Example
26. MS found for C22H16C1N7O2S (M+H)+ 478.1, 480.1 (Cl pattern).
EXAMPLE 43
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-oxopyrrolidin-1-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (43)
CI
,e )
N N-N H S~
O
N~,N ~
O
N O
The title compound was prepared by a similar procedure as described in Example
26. MS found for C23H19C1N603S (M+H)+ 495.1.
EXAMPLE 44
5-Chloro-N-((1-(2-nitro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide (44)
CI
N-N H S ~
NOZ O
O ~ Nv`~N \
/
I N
/
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SCHEME 2
cI
NOZ NOZ
NOZ N-N H S ~
~
~ \ F ~ ~ ` N3 ~ N _ ~N \
Br / Br / Br I/ O
2.1 2.2 2.3
cl
N-N H S ~
NOZ 0
O I ~ Nv `~N \
/
~ I N
2.4
Step 1:
To a solution of 1-Bromo-4-fluoro-3-nitrobenzene (2.44 g, 11 mmol) in 40 mL
DMSO was added sodium azide (1.44 g, 22 mmol). The mixture was stirred at RT
for 10
min. It was diluted with 500 mL ethyl acetate and washed with brine three
times. The
organic phase was dried and concentrated in vacuo to afford compound 2.2 (3.00
g, 100 %)
cleanly.
Step 2:
Compound 2.2 (all from previous step) was dissolved in 100 mL methanol. To it
were added compound 1.4 (3.3 g, 16.5 mmol), DBU (3.3 mL, 22 mmol) and Cul
(4.18 g, 22
mmol). The mixture was stirred overnight. It was diluted with 400 mL ethyl
acetate and
washed with brine twice. The organic phase was dried, concentrated and
purified using
flash column to afford compound 2.3 (1.07 g, 22 % for two steps). MS found for
Ci4H9BrC1N5O3S (M+H)+ 442.0, 444.0, 446Ø
Step 3:
Compound 2.3 (145 mg, 0.33 mmol) was dissolved in 5 mL dioxane and 1 mL
DMSO. To it were added 2-hydroxypyridine (125 mg, 1.32 mmol), N,N'-
dimethylethylenediamine (22 L, 0.2 mmol) and K3P04 (140 mg, 0.66 mmol). To it
was
then added Cul (32 mg, 0.17 mmol). The mixture was heated in 120 C bath in a
sealed tube
for 16 hrs. The mixture was then concentrated in vacuo and directly subjected
to reverse
phase preparative HPLC to isolate the title compound 2.4. MS found for
C19H13C1N604S
(M+H)+ 457.0, 459.0 (Cl pattern).
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EXAMPLE 45
N-((1-(2-Amino-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-yl)methyl)-
5-
chlorothiophene-2-carboxamide (45)
CI
N-N H S ~
NHZ O
O N
I ~ v `~N \
/
I N
To a solution of compound 2.4 (6 mg, 0.013 mmol) in 2 mL acetic acid and 2 mL
ethanol was added iron powder (5 mg, 0.08 mmol). The mixture was stirred in
100 C bath
for 30 min and directly subjected to reverse phase preparative HPLC to isolate
the title
compound. MS found for Ci9H15C1N602S (M+H)+ 427.1, 429.1 (Cl pattern).
EXAMPLE 46
1-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)urea (46)
NH2 ci
O1~-NH N=N H S ~
O I ~ Nv`~N \
N / O
0
N-((1-(2-Amino-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-yl)methyl)-
5-
chlorothiophene-2-carboxamide (43 mg, 0.10 mmol) was dissolved in 2 mL water
and 1 mL
DMSO. To it was added KOCN (82 mg, 1.0 mmol). The mixture was stirred in 60 C
bath
for 2 days and directly subjected to reverse phase preparative HPLC to isolate
the title
compound. MS found for C2oH16C1N703S (M+H)+ 470.1, 472.1 (Cl pattern).
EXAMPLE 47
N-((1-(2-Acetamido-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3 -triazol-4-
yl)methyl)-5-
chlorothiophene-2-carboxamide (47)
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CI
O NH N-N H S~
p ON'o
N-((1-(2-Amino-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3-triazol-4-
yl)methyl)-5-
chlorothiophene-2-carboxamide (43 mg, 0.10 mmol) was dissolved in 2 mL
anhydrous
DMSO. To it was added 120 L pyridine and 100 L acetyl chloride. The mixture
was in
60 C bath for 2 days in a sealed tube and directly subjected to reverse phase
preparative
HPLC to isolate the title compound. MS found for C21H17C1N603S (M+H)+ 469.1,
471.1
(Cl pattern).
EXAMPLE 48
N-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)isonicotinamide (48)
N
/
CI
O NH N-N H
O ~ Nv `~N
/ O
I N
The title compound was prepared by a similar procedure as described in Example
47. MS found for C25Hi8C1N703S (M+H)+ 532.1, 534.1 (Cl pattern).
EXAMPLE 49
N-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)-5-(2-
oxopyridin-1(2H)-yl)phenyl)nicotinamide (49)
N
CI
NH N-N H S ~
Nv`~N \
O ~ O
/
N
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The title compound was prepared by a similar procedure as described in Example
47. MS found for C25HigC1N703S (M+H)+ 532.1, 534.1 (Cl pattern).
EXAMPLE 50
5-Chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (50)
CI
S N=N H S ~
O N
v `~N \
I ~ O
/
I N
To a solution of compound 1.6 (690 mg, 1.6 mmol) was dissolved in 20 mL
anhydrous DMSO was added sodium thiomethoxide (225 mg, 3.2 mmol). The mixture
was
stirred in 100 C bath for 1 hr, and diluted with ethyl acetate. It was washed
with brine
three times, dried, concentrated and purified using flash column to afford the
title compound
(500 mg, 68 % yield) as a white solid. MS found for C20H16C1N502S2 (M+H)+
458.0, 460.0
(Cl pattern).
EXAMPLE 51
5-Chloro-N-((1-(2-(methylsulfoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (51)
cI
S'O N_N H S ~
O I ~ Nv N \
N / O
5-Chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-
4-yl)methyl)thiophene-2-carboxamide (500 mg, 1.1 mmol) was dissolved in 20 mL
methanol and 10 mL water. Oxone (677 mg, 1.1 mmol) was added in small
portions. The
mixture was stirred at RT for 45 min and directly subjected to reverse phase
prep HPLC to
isolate the title compound. MS found for C20H16C1N503S2 (M+H)+ 474.0, 476.0
(Cl
pattern).
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EXAMPLE 52
5-Chloro-N-((1-(2-(methylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (52)
o cI
I~N S
~ N14~N
O
N
5-Chloro-N-((1-(2-(methylsulfoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.21 mmol) was dissolved
in 10 mL
methanol and 5 mL water. Oxone (270 mg, 0.44 mmol) was added in small
portions. The
mixture was stirred at RT for overnight and directly subjected to reverse
phase prep HPLC
to isolate the title compound. MS found for C2oH16C1N504S2 (M+H)+ 490.0, 492.0
(Cl
pattern).
EXAMPLE 53
N-((1-(2-(2-Aminoethylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (53)
CI
CNHZ
N S N-N H S ~
O I ~ Nv N \
/ O
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SCHEME 3
H
F F N y Oll`<
F O NH2 O NZ NO2 S O
I~ NHZ /
N O 6N02
3.1 3.2 N
1.1 3.3
H
(NYO..]< ~NH2 ~NH2
S S
O NH2 O &NH2 O &N3
N N N 3.4 3.5 3.6
ci
CNHZ
S N-N H
O NO~,, N
/ O
3.7
Step 1:
The mixture of 2-fluoro-4-iodoaniline 1.1 (23.7 g, 100 mmol), 2-
hydroxypyridine
5 (19.0 g, 200 mmol), 8-hydroxyquinoline (2.9 g, 20 mmol), Cul (3.8 g, 20
mmol) and cesium
carbonate (65.2 g, 200 mmol) in 80 mL DMSO and 120 mL dioxane was stirred in
120 C
bath overnight. It was then concentrated in vacuo to remove dioxane. To the
residue was
added 300 mL brine. It was extracted with chloroform 300 mL six times. The
organic
extracts were combined, filtered, dried, and concentrated in vacuo to remove
three-fourth of
10 the chloroform. The resulting solid was collected by filtration, rinsed
with cold DCM, and
dried in vacuo to give compound 3.1 in 72 % yield (14.8 g). MS found for
CiiH9FN20
(M+H)+ 205.1.
Step 2:
To a stirring solution of trifluoroacetic anhydride (51 mL, 367 mmol) in 200
mL dry
DCM in a 1 liter flask in ice bath was added hydrogen peroxide (50 % water
solution, 23
mL, 367 mmol) dropwise. The mixture was stirred in ice bath for 90 min.
Compound 3.1
(7.5 g, 36.7 mmol) was then added in small portions over 10 min. The mixture
was stirred
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overnight, allowed to warm up to RT naturally. To the reaction mixture was
then added 300
mL brine. The organic phase was separated. The aqueous phase was extracted
with
chloroform 400 mL twice. The organic extracts were combined, dried and
concentrated in
vacuo to give compound 3.2 (9.1 g, 100 %). MS found for C11H7FN203 (M+H)+
235Ø
Step 3:
A mixture of compound 3.2 (0.93 g, 4.0 mmol), tert-butyl 2-
mercaptoethylcarbamate
(1.35 mL, 8.0 mmol) and DIEA (1.4 mL, 8. 0 mmol) in 20 mL DMSO was stirred in
90 C
bath for 1 hr. It was diluted with ethyl acetate and washed with saturated
ammonium
chloride twice and brine once. The organic phase was dried and concentrated in
vacuo to
give crude product 3.3. Crude compound 3.3 was then dissolved in 80 mL ethanol
and 40
mL acetic acid. To it was added iron powder (1.34 g, 24 mmol). The mixture was
stirred in
100 C bath for 90 min and diluted with acetonitrile. The mixture was filtered
through a
celite bed, and concentrated in vacuo to yield crude product 3.4. Crude
compound 3.4 was
then treated with 10 mL DCM and 10 mL TFA for 1 hr. The mixture was
concentrated in
vacuo and subjected to reverse phase preparative HPLC to isolate product 3.5
(0.7 g). MS
found for C13H15N30S (M+H)+ 262.1.
Step 4:
Compound 3.5 (0.7 g, 1.4 mmol) was dissolved in 10 mL TFA and stirred in ice
bath. To it was added powder NaNO2 (110 mg, 1.5 mmol) in small portions. The
mixture
was stirred for 40 min in ice bath. and chilled in ice bath. To the reaction
mixture was
added a chilled solution of sodium azide (190 mg, 2.8 mmol) in 2 mL water this
cold. The
mixture was stirred in ice bath for 1 hr and at RT for 30 min, and then
directly subjected to
reverse phase preparative HPLC to isolate compound 3.6 (540 mg). MS found for
C13H13N50S (M+H)+ 288.1.
Step 5:
Compound 3.6 (540 mg, 1.3 mmol) was dissolved in 20 mL methanol. To it were
added compound 1.4 (400 mg, 2.0 mmol), DBU (0.6 mL, 4.0 mmol) and Cul (513 mg,
2.7
mmol). The mixture was stirred at RT overnight, diluted with acetonitrile,
filtered through a
celite bed, concentrated and subjected to reverse phase preparative HPLC to
isolate the title
compound 3.7. MS found for C21H19C1N602S2 (M+H)+ 487.1, 489.1 (Cl pattern).
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EXAMPLE 54
N-((1-(2-(2-Aminoethylsulfoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (54)
CNHZ
SIO N=N H S CI
O I Nv N
N / O
The title compound was prepared from compound 3.7 using conditions similar to
those described in Example 51. MS found for C21H19C1N603S2 (M+H)+ 503.1, 505.1
(Cl
pattern).
EXAMPLE 55
N-((1-(2-(2-Aminoethylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (55)
O CI
CNHZ
N-N H S ~
SO O
O I Nv N \
/
N
The title compound was prepared from compound 3.7 using the same procedure
described for Example 52. MS found for C21H19C1N604S2 (M+H)+ 519.1, 521.1 (Cl
pattern).
EXAMPLE 56
5-Chloro-N-((1-(2-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide (56)
cl
O N-N H S ~
Nv N \
O I O
/
N
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SCHEME 4
F O O O
O \ NO2 O NO2 0 &NH2 O \ N3
N
/
3.2 4.1 4.2 4.3
CI
O N=N H S ~
~ O
NI \ N N \
/
4.4
Step 1:
To a solution of compound 3.2 (300 mg, 1.28 mmol) in 10 mL DMSO was added
sodium methoxide (280 mg, 5.12 mmol). The mixture was stirred in 100 C bath
for 10 min
and diluted with saturated ammonium chloride aq. solution. It was extracted
with ethyl
acetate. The organic extracts were combined, dried, concentrated in vacuo and
purified
using reverse phase preparative HPLC to afford compound 4.1 (55 %). MS found
for
Ci2HioN204 (M+H)+ 247.1.
Step 2:
Compound 4.1 (48 mg, 0.2 mmol) was dissolved in 6 mL ethanol and 3 mL acetic
acid and treated with iron powder (68 mg, 1.2 mmol) at 100 C for 30 min. The
mixture
was filtered and subjected to reverse phase preparative HPLC to isolate
compound 4.2 (70
%). MS found for C12H12N202 (M+H)+ 217.1.
Step 3:
Compound 4.2 (30 mg, 0.14 mmol) was dissolved in 2 mL TFA and stirred in ice
bath. To it was added sodium nitrite (12 mg, 0.16 mmol). The mixture was
stirred for 40
min. To it was then added an ice-cold solution of sodium azide (18 mg) in 1 mL
water.
The mixture was stirred in ice bath for 2 hr and subjected to reverse phase
preparative
HPLC to give compound 4.3 (40 %). MS found for C12HioN402 (M+H)+ 243.1.
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Step 4:
Compound 4.3 (10 mg, 0.04 mmol) was dissolved in 5 mL methanol. To it were
added compound 1.4 (12 mg, 0.06 mmol), DBU (18 L, 0.12 mmol) and Cul (15 mg,
0.08
mmol). The mixture was stirred at RT overnight, filtered and subjected to
reverse-phase
preparative HPLC to isolate the title compound 4.4. MS found for C20H16C1N503S
(M+H)+
442.1, 444.1 (Cl pattern).
EXAMPLE 57
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperidin-4-yloxy)phenyl)-1H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (57)
HN ci
~
O N-N H S
O Nv`~N \
NI O
I
SCHEME 5
O
F OA N O HN O HN
O
0 \ NO2 0 NO2 0 &NH2 N3
I/
N N I/ ~ N O I/
~ I I 00 /
3.2 5.1 5.2 5.3
HN CI
O N-N H S ~
NN ~
~ O I O
N
I 5.4
Step 1:
N-BOC-4-hydroxypiperidine (3.00 g, 14.8 mmol) was dissolved in 30 mL
anhydrous DMSO. To it was added sodium hydride (60 % in mineral oil, 0.60 g,
14.8
mmol) in small portions. The mixture was stirred at RT for 30 min. Compound
3.2 (1.74 g,
7.4 mmol) was dissolved in 20 mL anhydrous DMSO and was carefully added into
the
reaction mixture. The mixture was then stirred at 80 C for 90 min. It was
diluted with
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chloroform and washed with brine three times. The organic phase was dried,
concentrated
in vacuo and purified using flash column to give compound 5.1 (1.04 g, 34 %).
MS found
for C21H25N306 (M+H)+ 416.1.
Step 2:
Compound 5.1 (1.00 g, 2.4 mmol) was dissolved in 100 mL ethanol and 50 mL
acetic acid. It was treated with iron powder (0.81 g, 14.4 mmol) at 100 C for
90 min and
then diluted with acetonitrile and filtered through a celite bed. The filtrate
was concentrated
in vacuo and the residue was treated with 4N HC1 in dioxane for 2 hrs. The
mixture was
concentrated in vauo and treated with 200 mL 1N NaOH. It was extracted with
chloroform
twice. The organic extracts were combined, washed with brine, dried and
concentrated in
vacuo to give compound 5.2 (0.51 g, 74 %). MS found for C16H19N302 (M+H)+
286.1.
Step 3:
To a solution of compound 5.2 (0.51 g, 1.8 mmol) in 10 mL TFA in ice bath was
added sodium nitrite (125 mg, 1.8 mmol) in small portions. The mixture was
stirred in ice
bath for 30 min. To it was added an ice-cold solution of sodium azide (180 mg,
2.7 mmol)
in 2 mL water. The mixture was stirred in ice bath for 3 hrs and directly
subjected to
reverse phase preparative HPLC to isolate compound 5.3 (67 %). MS found for
C16H17N502 (M+H)+ 312.1.
Step 4:
Compound 5.3 (180 mg, 0.42 mmol) was dissolved in 20 mL methanol. To it were
added compound 1.4 (100 mg, 0.50 mmol), DBU (190 L, 1.3 mmol) and Cul (160
mg,
0.84 mmol). The mixture was stirred at RT overnight. It was diluted with
acetonitrile,
filtered through a celite bed, concentrated in vacuo and subjected to reverse
phase
preparative HPLC to isolate the title compound 5.4. MS found for C24H23C1N603S
(M+H)+
511.0, 513.0 (Cl pattern).
EXAMPLE 58
N-((1-(2-(1-Acetylpiperidin-4-yloxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (58)
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0
Aza CI
O N-N N ~
O I \ N ~
/ O
The title compound was prepared from 5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-
2-(piperidin-4-yloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-
carboxamide using
a similar procedure as described for Example 13. MS found for C26H25C1N604S
(M+H)+
553.1, 555.1 (Cl pattern).
EXAMPLE 59
4-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-5-
(2-
oxopyridin-1(2H)-yl)phenoxy)piperidine-l-carboxamide (59)
O
HZNA N ci
~
O N-N H S ~
N ~
O
O
U-1 A 10 The title compound was prepared from 5-chloro-N-((1-(4-(2-oxopyridin-
1(2H)-yl)-
2-(piperidin-4-yloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-
carboxamide using
the same procedure described for Example 15. MS found for C25H24C1N704S (M+H)+
554.1, 556.1 (Cl pattern).
EXAMPLE 60
5-Chloro-N-((1-(2-(1-methylpiperidin-4-yloxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (60)
~N
CI
N-N H S
NN
0 I 0
N
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The title compound was prepared using a similar procedure as described for
Example 57. MS found for C25H25C1N603S (M+H)+ 525.1, 527.1 (Cl pattern).
EXAMPLE 61
5-Chloro-N-((1-(2-(1-isopropylpiperidin-4-yloxy)-4-(2-oxopyridin- l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (61)
zaO N-N ci
H S ~
O Nv `~N \
O
I N
The title compound was prepared using a similar procedure as described for
Example 57. MS found for C27H29C1N603S (M+H)+ 553.1, 555.1 (Cl pattern).
EXAMPLE 62
5-Chloro-N-((1-(2-(2-oxopiperidin-4-yloxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (62)
0
HN CI
N O N-N S ~
O I ~ Nv N \
/ O
The title compound was prepared using a similar procedure as described for
Example 57. MS found for C24H21C1N604S (M+H)+ 525.1, 527.1 (Cl pattern).
EXAMPLE 63
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-4-yloxy)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (63)
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N;Ie
CI
H S ~
N=N
O I \ N
N / O
I
The title compound was prepared using a similar procedure as described for
Example 57. MS found for C24H17C1N603S (M+H)+ 505.1, 507.1 (Cl pattern).
EXAMPLE 64
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-3-yloxy)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (64)
N
~ I CI
O N-N H
N~,N
O I \ O
/
N
The title compound was prepared using a similar procedure as described for
Example 57. MS found for C24H17C1N603S (M+H)+ 505.1, 507.1 (Cl pattern).
EXAMPLE 65
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(tetrahydro-2H-thiopyran-4-
yloxy)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (65)
a CI
O N-N H S ~
N~,N ~
O I \ O
/
N
The title compound was prepared using a similar procedure as described for
Example 57. MS found for C24H22C1N503S2 (M+H)+ 528.1, 530.1 (Cl pattern).
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EXAMPLE 66
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1-dioxo-tetrahydro-2H-thiopyran-
4-
yloxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (66)
0
O%
N-N CI
H UTJ 5 The title compound was prepared from 5-chloro-N-((1-(4-(2-oxopyridin-
1(2H)-yl)-
2-(tetrahydro-2H-thiopyran-4-yloxy)phenyl)-1 H- 1,2,3 -triazol-4-
yl)methyl)thiophene-2-
carboxamide using a similar procedure as described for Example 12. MS found
for
C24H22C1N505S2 (M+H)+ 560.1, 562.1 (Cl pattern).
EXAMPLE 67
5-Chloro-N-((1-(2-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (67)
R
O N O
CI
v 'O N=N H S ~
N~~N ~
O I \ O
/
N
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SCHEME 6
O N O O N O O N O
R R R
F v 'O v O v 'O
0 \ NO2 O NO2 O NH2 O ` N3
N / ~ ~ N I~ ~ N ~ N I/
I
3.2 6.1 6.2 6.3
O N O
II
CI
v 'O N=N H S ~
~ O NV\~N ~
N O
I 6.4
Step 1:
N-(3-Hydroxypropyl)phthalimide (1.68 g, 8.2 mmol) was dissolved in 20 mL
anhydrous DMSO. To it was added sodium hydride (60 % in mineral oil, 0.33 g,
8.2
mmol). After stirring for 1 hr at RT, a solution of compound 3.2 (0.96 g, 4.1
mmol) in 10
mL anhydrous DMSO was added. The mixture was stirred for 1 hr in 80 C bath.
It was
diluted with chloroform and washed with brine three times. The organic phase
was dried,
concentrated and purified using flash column to afford compound 6.1 (45 %). MS
found for
C22H17N306 (M+H)+ 420.1.
Step 2:
Compound 6.1 (700 mg, 1.6 mmol) was dissolved in 30 mL ethanol and 15 mL
acetic acid. It was treated with iron powder (450 mg, 8.0 mmol) in 100 C bath
for 90 min.
It was diluted with acetonitrile, filtered through a celite bed, concentrated
and purified using
reverse phase HPLC to isolate compound 6.2 (57 %). MS found for C22H19N304
(M+H)+
390.1.
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Step 3:
Compound 6.2 (200 mg, 0.51 mmol) was dissolved in 7 mL TFA and stirred in ice
bath. To it was added sodium nitrite (36 mg, 0.51 mmol). The mixture was
stirred in ice
bath for 30 min. Then an ice-cold solution of sodium azide (50 mg, 0.77 mmol)
in 1 mL
water was added. The mixture was stirred for 2 hrs in ice bath, diluted with
300 mL ethyl
acetate, washed with brine twice and sodium bicarbonate saturated aq. solution
once. The
organic phase was dried and concentrated in vacuo to give compound 6.3 in
quantitative
yield. MS found for C22H17N504 (M+H)+ 416.1.
Step 4:
Compound 6.3 (0.51 mmol) was dissolved in 10 mL methanol. To it were added
compound 1.4 (101 mg, 0.51 mmol), DBU (160 L, 1.02 mmol) and Cul (200 mg,
1.02
mmol). The mixture was stirred at RT overnight, diluted with acetonitrile,
filtered through a
celite bed, concentrated in vacuo and subjected to direct reverse phase
preparative HPLC to
isolate title compound 6.4. MS found for C30H23C1N605S (M+H)+ 615.1, 617.1 (Cl
pattern).
EXAMPLE 68
N-((1-(2-(3 -Aminopropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-
4-
yl)methyl)-5-chlorothiophene-2-carboxamide (68)
NH2 ci
v 'O N=N H S ~
O I ~ Nv N
/ O
I N
To a solution of compound 6.4 (16 mg, 0.026 mmol) in 10 mL methanol was added
hydrazine monohydrate (15 L, 0.30 mmol). The mixture was stirred at 80 C for
2 hrs and
then directly subjected to reverse phase preparative HPLC to isolate the title
compound.
MS found for C22H21C1N603S (M+H)+ 485.1, 487.1 (Cl pattern).
EXAMPLE 69
N-((1-(2-(3-Acetamidopropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (69)
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O
HN~ CI
v 'O N=N H S
p I\ N ~
I ~
N / O
The title compound was prepared from N-((1-(2-(3-aminopropoxy)-4-(2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide
(as
shown in Example 68) using a similar procedure as described in Example 13. MS
found for
C24H23C1N604S (M+H)+ 527.1, 529.1 (Cl pattern).
EXAMPLE 70
1-(3-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-
5-(2-
oxopyridin-1(2H)-yl)phenoxy)propyl)urea (70)
O
HN'k NH2 CI
v 'O N=N S oJT1>
The title compound was prepared from N-((1-(2-(3-aminopropoxy)-4-(2-oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide
using a
similar procedure as described in Example 15. MS found for C23H22C1N704S
(M+H)+
528.1, 530.1 (Cl pattern).
EXAMPLE 71
N-((1-(2-(2-Aminoethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (71)
CI
H2N,,,-,0 N=N H S ~
O I \ N~,N ~
/ O
I N
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The title compound was prepared using a similar procedure as described in
Example
68. MS found for C21H19C1N603S (M+H)+ 471.1, 473.1 (Cl pattern).
EXAMPLE 72
N-((1-(2-(2-Acetamidoethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (72)
o~
cl
HN,,,^,O N-N H S
N ~
O I ~ Nv `~N \
/ O
The title compound was prepared using a similar procedure as described in
Example
69. MS found for C23H21C1N604S (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 73
1-(2-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-
5-(2-
oxopyridin-1(2H)-yl)phenoxy)ethyl)urea (73)
O~NHZ
CI
HN~~~O N=N H S ~
O
NI ~ Nv `~N \
/ O
The title compound was prepared using a similar procedure as described in
Example
70. MS found for C22H2OC1N704S (M+H)+ 514.1, 516.1 (Cl pattern).
EXAMPLE 74
5-Chloro-N-((1-(2-(3-hydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (74)
OH CI
Ll..'O N=N H S ~
Nv `~N \
O I O
N
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SCHEME 7
F OH OH OH
O ~ NO2 O NO2 O ` NH2 O ~ N3
N I/ N ~ 1 N I/ 0- N I
I
3.2 7.1 7.2 7.3
O,H OH CI
v~0 v'O N=N H S~
O O ~ ---- 40- N O
7.4 7.5
Step 1:
Compound 3.2 (1.00 g, 4.27 mmol) was dissolved in 10 mL dioxane and 10 mL
water. It was treated with sodium hydroxide (0.34 g, 8.6 mmol) at 60 C for 2
hr. It was
acidified using 2N HC1 till pH=1. It was extracted with ethyl acetate twice.
The organic
extracts were combined, dried and concentrated in vacuo to afford compound 7.1
in 96 %
yield (0.95 g). MS found for CiiHgN204 (M+H)+ 233Ø
Step 2:
Compound 7.1 (0.95 g, 4.1 mmol) was stirred in 60 mL ethanol and 20 mL water.
To it were added ammonium chloride (2.2 g, 41 mmol) and indium powder (1.9 g,
16.4
mmol). The mixture was heated in 100 C bath for 6 hrs. It was concentrated in
vacuo to
remove ethanol. The residue was titrated with saturated sodium carbonate aq.
solution till
pH=7.5. The mixture was extracted with CHC13/iPrOH (3:1) four times. The
organic
extracts were combined, dried and concentrated in vacuo to give compound 7.2
in 80 %
yield (0.66 g). MS found for CiiHioN202 (M+H)+ 203.1.
Step 3:
Compound 7.2 (0.66 g, 3.2mmo1) was dissolved in 50 mL concentrated HC1 and
stirred in ice bath. To it was added an ice-cold solution of sodium nitrite
(0.33 g, 4.8 mmol)
in 4 mL water dropwise. The mixture was stirred for 40 min. Then an ice-cold
solution of
sodium azide (0.62 g, 9.6 mmol) in 5 mL water was added. The mixture was
stirred
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overnight. The mixture was then extracted with ethyl acetate three times. The
combined
organic extracts were washed with brine, dried and concentrated in vacuo to
give compound
7.3 (0.63 g, 86 %). MS found for CiiHgN402 (M+H)+ 229.1.
Step 4:
Compound 7.3 (55 mg, 0.24 mmol) was dissolved in 3 mL DMF. To it were added
K2C03 (132 mg, 0.96 mmol) followed by 3-bromo-l-propanol (78 L, 0.96 mmol).
The
mixture was stirred overnight at RT and then directly subjected to flash
column to isolate
compound 7.4 (39 mg, 57 %). MS found for Ci4H14N403 (M+H)+ 287.1.
Step 5:
Compound 7.4 (39 mg, 0.14 mmol) was dissolved in 5 mL methanol. To it were
added compound 1.4 (28 mg, 0.14 mmol), DBU (42 L, 0.28 mmol) and Cul (53 mg,
0.28
mmol). The mixture was stirred overnight, diluted with acetonitrile, filtered
through a celite
bed, concentrated and subjected to reverse phase preparative HPLC to isolate
the title
compound 7.5. MS found for C22H20C1N504S (M+H)+ 486.1, 488.1 (Cl pattern).
EXAMPLE 75
5-Chloro-N-((1-(2-(2-hydroxyethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-
4-yl)methyl)thiophene-2-carboxamide (75)
CI
HO--~O N=N H S ~
o'T1
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C21H18C1N504S (M+H)+ 472.1, 474.1 (Cl pattern).
EXAMPLE 76
5-Chloro-N-((1-(2-(2-methoxyethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-
4-yl)methyl)thiophene-2-carboxamide (76)
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CI
-00'O"'~0 N-N H p
O `~N N / O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H20C1N504S (M+H)+ 486.1, 488.1 (Cl pattern).
EXAMPLE 77
5-Chloro-N-((1-(2-(3-methoxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (77)
O/
CI
v 'O N=N H S
Nv N
O O
/
N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C23H22C1N504S (M+H)+ 500.1, 502.1 (Cl pattern).
EXAMPLE 78
5-Chloro-N-((1-(2-((R)-2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (78)
OH CI
v _O N=N H S
O OH N~,N ~
N / O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H2OC1N505S (M+H)+ 502.1, 504.1 (Cl pattern).
EXAMPLE 79
5-Chloro-N-((1-(2-((S)-2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (79)
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OH CI
Ire---O N=N H S ~
O OII.-Y N~,N ~
O
N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H2OC1N505S (M+H)+ 502.1, 504.1 (Cl pattern).
EXAMPLE 80
5-Chloro-N-((1-(2-(2-(methylsulfonyl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (80)
O~ O CI
N=N H S ~
O I Nv N \
N O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H2OC1N505S2 (M+H)+ 534.1, 536.1 (Cl pattern).
EXAMPLE 81
5 -Chloro-N-((1-(2-(2-(aminosulfonyl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
l H-1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (81)
OO CI
H2N' N=N H N S ~
O I ~ Nv N \
/ O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C21H19C1N605S2 (M+H)+ 535.1, 537.1 (Cl pattern).
EXAMPLE 82
5-Chloro-N-((1-(2-(2-(ethylsulfonyl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
l H-1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (82)
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OO CI
N=N H
O I ~ Nv `~N
/ O
I N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C23H22C1N505S2 (M+H)+ 548.1, 550.1 (Cl pattern).
EXAMPLE 83
5-Chloro-N-((1-(2-(3-(methylsulfonyl)propoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (83)
CI
N-N H S
OO N~~ N ~
O I\
/ 0
I N
/
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C23H22C1N505S2 (M+H)+ 548.1, 550.1 (Cl pattern).
EXAMPLE 84
5-Chloro-N-((1-(2-(3-(aminosulfonyl)propoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (84)
CI
H2N~ O N=N H S
O~O
O I ~ N
N ~
/ O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H21C1N605S2 (M+H)+ 549.1, 551.1 (Cl pattern).
EXAMPLE 85
5-Chloro-N-((1-(2-(2-(dimethylamino)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
l H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (85)
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~ CI
/ N N=N H
N
p
N O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C23H23C1N603S (M+H)+ 499.1, 501.1 (Cl pattern).
EXAMPLE 86
5-Chloro-N-((1-(2-(2-(dimethyl(dimethylamino)amino)ethoxy)-4-(2-oxopyridin-
1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (86)
\+/ CI
i O N-N H S ~
O
NI ~ Nv `~N \
/ O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C27H33C1N703S M+ 570.1.
EXAMPLE 87
5-Chloro-N-((1-(2-(2-(methylamino)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (87)
H CI
N=N H S ~
O I \ Nv `~N \
/ O
I N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C22H21C1N603S (M+H)+ 485.1, 587.1 (Cl pattern).
EXAMPLE 88
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
1 H-1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (88)
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CI
ONO N=N H
O I ~ Nv N
/ O
N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C25H25C1N603S (M+H)+ 525.1, 527.1 (Cl pattern).
EXAMPLE 89
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(piperidin-1-yl)ethoxy)phenyl)-
1H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (89)
CI
N-,~O N=N
~H S
O NN \
O
I N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C26H27C1N603S (M+H)+ 539.1, 541.1 (Cl pattern).
EXAMPLE 90
5-Chloro-N-((1-(2-(2-morpholinoethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (90)
O CI
NN=N H
oTJ'>
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C25H25C1N604S (M+H)+ 541.1, 543.1 (Cl pattern).
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EXAMPLE 91
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(pyridin-4-yl)ethoxy)phenyl)-1
H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (91)
N;" I
CI
O N-N H S
O ~N ~
O
N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C26H21C1N603S (M+H)+ 533.1, 535.1 (Cl pattern).
EXAMPLE 92
5-Chloro-N-((1-(2-(3-(dimethylamino)propoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (92)
CI
i 'O*~O N-N H S
O I \ N ~
O
N
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C24H25C1N603S (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 93
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(3-(pyrrolidin-1-
yl)propoxy)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (93)
CI
GN^~~O N=N H A
O I ~N N O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C26H27C1N603S (M+H)+ 539.1, 541.1 (Cl pattern).
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EXAMPLE 94
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(3 -(piperidin-1-
yl)propoxy)phenyl)-1 H-1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (94)
CI
,-N~~O N=N H
G N S ~
N / N ~
o ~ \
/ O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C27H29C1N603S (M+H)+ 553.1, 555.1 (Cl pattern).
EXAMPLE 95
5-Chloro-N-((1-(2-(3-morpholinopropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (95)
CI
N=N H
OJ N~~ I
O N o
N
J O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C26H27C1N604S (M+H)+ 555.1, 557.1 (Cl pattern).
EXAMPLE 96
2-(2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-5-
(2-
oxopyridin-1(2H)-yl)phenoxy)acetic acid (96)
CI
Oool~O N=N H S
I ~
0 0 y Nv `~N \
/ O
N
O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C21H16C1N505S (M+H)+ 486.1, 488.1 (Cl pattern).
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EXAMPLE 97
N-((1-(2-(2-Amino-2-oxoethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (97)
CI
H2N0 N=N H
0 0 NN
N / O
I
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C21H17C1N604S (M+H)+ 485.1, 487.1 (Cl pattern).
EXAMPLE 98
N-((1-(2-((1 H-Tetrazol-5-yl)methoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (98)
N=N
HN N
CI
O N-N H
O I Nv `~N
N / O
The title compound was prepared using a procedure similar to that described in
Example 74. MS found for C21H16C1N903S (M+H)+ 510.1, 512.1 (Cl pattern).
EXAMPLE 99
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(trifluoromethoxy)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (99)
F F ci
F>'-O N=N H S
~
O N \
Nv
N O
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SCHEME 8
cl
F3C.0 F3C.0 F3C'0 N=N S
= H \
NH2 ~ ~ N3 ~ I ~ NN
I ~/ I ~/ I / O
8.1 8.2 8.3
F F CI
H S ~
F~O N-N
O N
O
8.4
Step 1:
4-Iodo-2-trifluoromethoxyaniline (1.68 g, 5.5 mmol) was stirred in 40 mL conc.
HC1
in ice bath. To it was added an ice-cold solution of sodium nitrite (0.57 g,
8.3 mmol) in 2
mL water dropwise. The mixture was stirred at RT for 30 min. Then an ice-cold
solution
of sodium azide (1.08 g, 16.6 mmol) in 5 mL water was added. The mixture was
stirred
overnight before being extracted with ethyl acetate twice. The organic
extracts were
combined, washed with brine, dried, and concentrated in vacuo to afford
compound 8.2
(1.69 g, 93 %).
Step 2:
Compound 8.2 (1.69 g, 5.1 mmol) was dissolved in 50 mL methanol. To it were
added compound 1.4 (1.54 g, 7.7 mmol), DBU (1.52 mL, 10.2 mmol) and Cul (1.94
g, 10.2
mmol). The mixture was stirred overnight, diluted with acetonitrile, filtered
through celite
bed, concentrated, purified using flash column to give compound 8.3 (1.85 g,
69 %). MS
found for C15H9C1F3IN402S (M+H)+ 529Ø
Step 3:
Compound 8.3 (180 mg, 0.34 mmol) was dissolved in 5 mL dioxane and 1 mL
DMSO in a sealed tube. To it were added 2-hydroxypyridine (130 mg, 1.36 mmol),
N,N'-
dimethylethylenediamine (22 L, 0.2 mmol), K3P04 (144 mg, 0.68 mmol) and Cul
(32 mg,
0.17 mmol). The mixture was stirred at 120 C for 16 hrs, filtered,
concentrated and
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subjected to reverse phase preparative HPLC to isolate the title compound 8.4.
MS found
for C20H13C1F3N503S (M+H)+ 496.0, 498.0 (Cl pattern).
EXAMPLE 100
2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol- l -yl)-5-(2-
oxopyridin-
1(2H)-yl)benzoic acid (100)
CI
H O
N =N N
O
N O
SCHEME 9
CI
O O
/O O ,O O L
N-N H
\ NH2 \ N3 N
/ I/ O
9.1 9.2 9.3
CI
HO O
N-N H
~ I \
O N N
O
9.4
Step 1:
Methyl 2-amino-5-iodonezoate (3.00 g, 10.8 mmol) was stirred in 35 mL TFA in
ice
bath. To it was added sodium nitrite (820 mg, 12 mmol) in small portions. The
mixture
was stirred in ice bath for 40 min. To it was added an ice-cold solution of
sodium azide
(1.41 g, 21.6 mmol) in 8 mL water. The mixture was stirred for 3 hrs, diluted
with ethyl
acetate (500 mL), washed with brine three times, dried, and concentrated in
vacuo to give
compound 9.2 in quantitative yield.
Step 2:
Compound 9.2 (10.8 mmol) was dissolved in 200 mL methanol. To it were added
compound 1.4 (2.58 g, 13.0 mmol), DBU (4.8 mL, 32 mmol) and Cul (4.1 g, 21
mmol). The
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mixture was stirred overnight, diluted with 600 mL ethyl acetate, filtered
through a celite
bed. The filtrate was washed with saturated ammonium chloride aq. solution and
brine,
dried, and concentrated in vacuo to give compound 9.3 in quantitative yield.
MS found for
C16H12C1IN403S (M+H)+ 503.0, 505.0 (Cl pattern).
Step 3:
Compound 9.3 (2.00 g, 4.0 mmol) was dissolved in 50 mL DMSO. To it were
added 2-hydroxypyridine (0.76 g, 8.0 mmol), 8-hydroxyquinoline (174 mg, 1.2
mmol),
cesium carbonate (2.61 g, 8.0 mmol) and Cul (230 mg, 1.2 mmol). The mixture
was stirred
at 120 C for 18 hrs. It was then filtered and directly subjected to reverse
phase preparative
HPLC to isolate the title compound 9.4. MS found for C20H14C1N504S (M+H)+
456.0,
458.0 (Cl pattern).
EXAMPLE 101
N-((1-(2-Carbamoyl-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-triazol-4-
yl)methyl)-5 -
chlorothiophene-2-carboxamide (101)
CI
H2N O
N =N N
O
O
I
2-(4-((2-Chlorothiophene-5-carboxamido)methyl)-1 H-1,2,3-triazol-1-yl)-5 -(2-
oxopyridin-1(2H)-yl)benzoic acid (13 mg, 0.03 mmol) was dissolved in 2 mL DMF.
To it
were added ammonia (0.5M in dioxane, 180 L, 0.09 mmol), DIEA (26 L, 0.15
mmol)
and PyBOP (47 mg, 0.09 mmol) in order. The mixture was stirred at RT for 17
hrs and
directly subjected to reverse phase preparative HPLC to isolate the title
compound. MS
found for C20H15C1N603S (M+H)+ 455.1, 457.1 (Cl pattern).
EXAMPLE 102
5-Chloro-N-((1-(2-(methylcarbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-
4-yl)methyl)thiophene-2-carboxamide (102)
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~ CI
HN O
N =N N
~i
p \
N O
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C21Hi7C1N603S (M+H)+ 469.1, 471.1 (Cl pattern).
EXAMPLE 103
5-Chloro-N-((1-(2-(dimethylcarbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (103)
1 CI
00N
N-N H
O I ~ Nv `~ N
/ O
N
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C22H19C1N603S (M+H)+ 483.1, 485.1 (Cl pattern).
EXAMPLE 104
N-((1-(2-((2-Hydroxyethyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3 -triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (104)
H CI
HO^~N O N=N H S~
O I \ Nv `~N \
N /
0
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C22H19C1N604S (M+H)+ 499.1, 501.1 (Cl pattern).
EXAMPLE 105
N-((1-(2-((3-Hydroxypropyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (105)
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H CI
O,,,,~~ N O
N=N N
O I ` S ~
~
/ 0
I N
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C23H21C1N604S (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 106
N-((1-(2-((2-Methoxyethyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (106)
H CI
\O^~N O N=N H
0 N / 0
I N
/
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C23H21C1N604S (M+H)+ 513.1, 515.1 (Cl pattern).
EXAMPLE 107
N-((1-(2-((2-Aminoethyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (107)
H CI
H2N^/N O N_N H S~
O N,,,N ~
I/
N O
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C22H2OC1N703S (M+H)+ 498.1, 500.1 (Cl pattern).
EXAMPLE 108
N-((1-(2-((2-Amino-2-oxoethyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (108)
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O H cl
H2NAIIIN O N_N H S~
O I ~ Nv N \
/ O
N
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C22HigC1N704S (M+H)+ 512.1, 514.1 (Cl pattern).
EXAMPLE 109
N-((1-(2-((2-(Dimethylamino)ethyl)carbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-
1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (109)
H CI
ii N N=N H
0 JL
0
N
/
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C24H24C1N703S (M+H)+ 526.1, 528.1 (Cl pattern).
EXAMPLE 110
5-Chloro-N-((1-(2-(methyl(2-(methylamino)ethyl)carbamoyl)-4-(2-oxopyridin-
1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (110)
~ CI
HN O N=N
N O S ~
N H
I ~ ~N ~
/
N 0
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C24H24C1N703S (M+H)+ 526.1.
EXAMPLE 111
5-Chloro-N-((1-(2-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-4-(2-oxopyridin-
1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (111)
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CI
i~iN N=N H S ~
O N~~N ~
/ ON0
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C25H26C1N703S (M+H)+ 540.1.
EXAMPLE 112
N-((1-(2-(3-aminopropylcarbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (112)
H CI
H2N,,,-,,~,N O
N=N H S ~
O N~ Nv vN \
N 0
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C23H22C1N703S (M+H)+ 512.1.
EXAMPLE 113
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazine- l -carbonyl)phenyl)-1
H-1,2, 3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (113)
HN CI
0 ~ N~,N ~
;I-o.&"*" N-N H S ~
N O
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C24H22C1N703S (M+H)+ 524.1, 526.1 (Cl pattern).
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EXAMPLE 114
5-Chloro-N-((1-(2-(2-oxopiperazine-4-carbonyl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (114)
HN""') ci
N O N-N H
O NN
N 5 The title compound was prepared using a similar procedure as described in
Example
101. MS found for C24H20C1N704S (M+H)+ 538.1, 540.1 (Cl pattern).
EXAMPLE 115
5-Chloro-N-((1-(2-(4-hydroxypiperidine-l -carbonyl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (115)
HO
CI
N
N-N H S ~
O NN
fl, I
O
I
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C25H23C1N604S (M+H)+ 539.1.
EXAMPLE 116
1-(2-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-5-
(2-
oxopyridin-1(2H)-yl)benzoyl)piperidine-4-carboxamide (116)
0
H2N ci
N O
N =N N
O I\
/ O
118
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The title compound was prepared using a similar procedure as described in
Example
101. MS found for C26H24C1N704S (M+H)+ 566.1.
EXAMPLE 117
N-((1-(2-(((1 H-Tetrazol-5-yl)methyl)carbamoyl)-4-(2-oxopyridin- l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (117)
'N NH H CI
N=N~N
N-N H S
O
NI ~ Nv `~N \
/ O
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C22Hi7C1Nio03S (M+H)+ 537.1, 539.1 (Cl pattern).
EXAMPLE 118
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-4-ylcarbamoyl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (118)
r ~ N O CI
N_N H
O Nv N
/ O
N
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C25H18C1N703S (M+H)+ 532.1, 534.1 (Cl pattern).
EXAMPLE 119
5-Chloro-N-((1-(2-(hydroxymethyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -
triazol-4-
yl)methyl)thiophene-2-carboxamide (119)
CI
HO
N-N H S ~
O Nv `~N \
O
N
119
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SCHEME 10
CI CI
/O O N=N H HO N-N H
IV_ N N
O O
9.3 10.1
CI
HO
N-N N
O
O
10.2
Step 1:
To a solution of compound 9.3 (1.61 g, 3.2 mmol) in 60 mL anhydrous THF was
added lithium borohydride (2.0 M in THF, 4.8 mL, 9.6 mmol) dropwise. The
mixture was
stirred at RT overnight. To it was then added 2N HC1 and 500 mL ethyl acetate.
The
organic phase was separated and washed with brine twice. It was dried,
concentrated, and
purified using flash column to afford compound 10.1 in quantitative yield. MS
found for
C15H12C1IN402S (M+H)+ 475.0, 477.0 (Cl pattern).
Step 2:
Compound 10.1 (128 mg, 0.27 mmol) was dissolved in 5 mL DMSO in a sealed
tube. To it were added 2-hydroxypyridine (51 mg, 0.54 mmol), 8-hydroxypyridine
(16 mg,
0.11 mmol), cesium carbonate (176 mg, 0.54 mmol) and Cul (21 mg, 0.11 mmol).
The
mixture was stirred at 120 C for 17 hrs. It was then directly subjected to
reverse phase
preparative HPLC to isolate the title compound 10.2. MS found for
C2oH16C1N503S
(M+H)+ 442.1, 444.1 (Cl pattern).
EXAMPLE 120
N-((1-(2-(Aminomethyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H- 1,2,3 -triazol-4-
yl)methyl)-
5-chlorothiophene-2-carboxamide (120)
cl
H2N
N-N H S ~
O Nv `~N \
O
I N
120
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SCHEME 11
ci ci
HO ci
N-N H N-N H
O Nv vN O I\ Nv vN
I N / O ~ I N / O ~
10.2 / 11.1
ci ci
N3 N-N H H2N N-N H
O Nv v N O N% vN
I N / O ~ I N / O
11.2 11.3
Step 1:
To a solution of compound 10.2 (10 mg, 0.022 mmol) in 2 mL anhydrous
acetonitrile was added 0.5 mL thionyl chloride. The mixture was stirred at RT
for 20 min.
To it was added 20 mL methanol. The mixture was concentrated in vacuo to
afford crude
compound 11.1. MS found for C20H15C12N502S (M+H)+ 460.0, 462.0 (Cl pattern).
Step 2:
To a solution of crude compound 11.1 in 3 mL DMSO was added sodium azide (10
mg). The mixture was stirred at RT for 2 hrs and directly subjected to reverse
phase
preparative HPLC to isolate compound 11.2 in quantitative yield. MS found for
C2oH15C1N802S (M+H)+ 467.1, 469.1 (Cl pattern).
Step 3:
Compound 11.2 (10 mg, 0.22 mmol) was dissolved in 4 mL ethanol and 2 mL acetic
acid. It was treated with iron powder (10 eq) at 100 C for 15 min. The
mixture was dilute
with acetonitrile, filtered through a celite bed, concentrated and subjected
to reverse phase
preparative HPLC to isolate the title compound 11.3. MS found for
C2oH17C1N602S
(M+H)+ 441.1, 443.1 (Cl pattern).
EXAMPLE 121
5-Chloro-N-((1-(2-((dimethylamino)methyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (121)
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cl
N-N H S ~
O Nv N \
O
N
The title compound was prepared using a procedure similar to that used for
preparing compound 11.2 as described in Example 120. MS found for
C22H21C1N602S
(M+H)+ 469.1, 471.1 (Cl pattern).
EXAMPLE 122
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperidin-1-ylmethyl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (122)
ON
N-N H S cl
~
O I N N \
GN O
The title compound was prepared using a procedure similar to that used for
preparing compound 11.2 as described in Example 120. MS found for
C25H25C1N602S
(M+H)+ 509.1, 511.1 (Cl pattern).
EXAMPLE 123
5-Chloro-N-((1-(2-(methylthiomethyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (123)
cl
/s
N-N H
O S
NN
O
I
The title compound was prepared using a procedure similar to that used to
prepare
compound 11.2 as described in Example 120. MS found for C21HigC1N502S2 (M+H)+
472.1, 474.1 (Cl pattern).
122
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EXAMPLE 124
5-Chloro-N-((1-(2-(methylsulfonylmethyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (124)
O%,/O ci
/ N-N H S ~
O I \ NN ~
N / O
The title compound was prepared from 5-chloro-N-((1-(2-(methylthiomethyl)-4-(2-
oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-
carboxamide using
a similar procedure as described in Example 12. MS found for C21H18C1N504S2
(M+H)+
504.0, 506.0 (Cl pattern).
EXAMPLE 125
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-4-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (125)
N
CI
N-N H S ~
0 I N N
~
GN O
SCHEME 12
N
/
Br
O \ NH2 O \ NH2~ O NH2
NHZ I/ N I/ N
12.1 12.2 12.3 12.4
N N
CI
N-N H
O N3 0 4,0~,,N
N N O
~ /
12.5 12.6
123
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Step 1:
4-lodoaniline (12.1, 10.0 g, 45.6 mmol) was dissolved in 80 mL dioxane and 40
mL
DMSO. To it were added 2-hydroxypyridine (8.68 g, 91.2 mmol), 8-
hydroxyquinoline
(1.32 g, 9.12 mmol), cesium carbonate (30.0 g, 91.2 mmol) and Cul (1.73 g,
9.12 mmol).
The mixture was stirred at 120 C for 6 hrs. It was filtered, concentrated,
and taken into 800
mL chloroform. The organic solution washed with brine twice and concentrated
to its 1/4
volume. The solid crashed out was isolated by filtration, washed with cold
DCM, and dried
in vacuo to give compound 12.2 (4.62 g, 54 %). MS found for CiiHioN20 (M+H)+
187.1.
Step 2:
To a solution of compound 12.2 (7.44 g, 40 mmol) in 100 mL DMF was added NBS
(14.2 g, 80 mmol) in small portions. The mixture was stirred at RT overnight.
It was
diluted with 1000 mL ethyl acetate, washed with brine three times, dried,
concentrated and
subjected to flash column chromatography using 5 % methanol in DCM to isolate
compound 12.3 (7.20 g, 68 %). MS found for CiiH9BrN2O (M+H)+ 265.0, 267Ø
Step 3:
Compound 12.3 (400 mg, 1.5 mmol), 4-pyridineboronic acid (185 mg, 1.5 mmol)
and cesium carbonate (1.47 g, 4.5 mmol) were stirred in a mixture 2 mL n-
butanol, 8 mL
toluene and 4 mL water. The mixture was degassed by argon stream for 5 min.
Pd(Ph3P)4
(350 mg, 0.3 mmol) was then added and the mixture was stirred under argon at
80 C
overnight. It was diluted with 150 mL chloroform, washed with sat sodium
carbonate aq
solution twice, dried, concentrated and purified using flash column with 10 %
methanol in
DCM to give compound 12.4 (86 mg, 22 %). MS found for C16H13N30 (M+H)+ 264.1.
Step 4:
To a solution of compound 12.4 (86 mg, 0.33 mmol) in 5 mL TFA in ice bath was
added sodium nitrite (34 mg, 0.49 mmol). The mixture was stirred in ice bath
for 30 min.
To it was added an ice-cold solution of sodium azide (65 mg, 1.0 mmol) in 1 mL
water.
The mixture was stirred for 2 hrs and directly subjected to reverse phase
preparative HPLC
to give compound 12.5 in a quantitative yield. MS found for C16HiiN50 (M+H)+
290.1.
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Step 5:
Compound 12.5 from the previous step was dissolved in 10 mL methanol. To it
were added compound 1.4 (140 mg, 0.70 mmol), DBU (105 L, 0.70 mmol) and Cul
(133
mg, 0.70 mmol). The mixture was stirred overnight, diluted with acetonitrile,
filtered
through a celite bed, concentrated and subjected to reverse phase preparative
HPLC to
isolated the title compound 12.6. MS found for C24H17C1N602S (M+H)+ 489.1,
491.1 (Cl
pattern).
EXAMPLE 126
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-3-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (126)
~ N ci
N-N H
O I Nv ,N
/ O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C24H17C1N602S (M+H)+ 489.1, 491.1 (Cl pattern).
EXAMPLE 127
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyrimidin-5-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (127)
~^N CI
/
N-N H
O I Nv `~N \
N / O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C23H16C1N7O2S (M+H)+ 490.1, 492.1 (Cl pattern).
125
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EXAMPLE 128
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1 H-pyrazol-3-yl)phenyl)-1 H-
1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide (128)
NH ci
N =N N
O S ~
~
N O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C22H16C1N7O2S (M+H)+ 478.1, 480.1 (Cl pattern).
EXAMPLE 129
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((4-aminophenyl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (129)
NH2
CI
/
N-N H
0 NNO~I~ N
N / O
I
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25H19C1N602S (M+H)+ 503.1, 505.1 (Cl pattern).
EXAMPLE 130
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((4-hydroxyphenyl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (130)
OH
ci
/
N =N S
N
~i
O I\
N / O
126
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The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25HigC1N503S (M+H)+ 504.1, 506.1 (Cl pattern).
EXAMPLE 131
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((3-aminophenyl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (131)
\ NH2
CI
N-N H S
NO~,, N
p 1
N / O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25H19C1N602S (M+H)+ 503.1, 505.1 (Cl pattern).
EXAMPLE 132
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-((3-hydroxyphenyl)phenyl)-1H-1,2,3-
triazol-
4-yl)methyl)thiophene-2-carboxamide (132)
OH
~ CI
/
N-N H
~ O
O I \ Nv `~N
/
N
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25HigC1N503S (M+H)+ 504.1, 506.1 (Cl pattern).
EXAMPLE 133
5-Chloro-N-((1-(2-(2-chloropyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (133)
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N CI
~ CI
N-N H
O Nv `~N
O
N
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C24H16C12N602S (M+H)+ 523.0, 525.0 (Cl pattern).
EXAMPLE 134
5-Chloro-N-((1-(2-(2-fluoropyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (134)
N F
CI
N =N N S ~
~
O I
N O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C24H16C1FN602S (M+H)+ 507.1, 509.1 (Cl pattern).
EXAMPLE 135
5-Chloro-N-((1-(2-(6-chloropyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (135)
CI
N CI
/
N-N H
O Nv ~ N
O
N
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C24H16C12N602S (M+H)+ 523.0, 525.0 (Cl pattern).
128
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EXAMPLE 136
5-Chloro-N-((1-(2-(6-fluoropyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide(136)
F
N
CI
N-N N
O ~ ~,
O
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C24H16C1FN602S (M+H)+ 507.1, 509.1 (Cl pattern).
EXAMPLE 137
5-Chloro-N-((1-(2-(2-hydroxypyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (137)
N OH
. CI
N-N H
O Nv `~N
N / O
5 -Chloro-N-((1-(2-(2-fluoropyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (10 mg, 0.02 mmol) was
dissolved in 2
mL DMSO and 2 mL water in a sealed tube. To it was added cesium carbonate (100
mg,
0.3 mmol) and the mixture was stirred overnight at 120 C. It was directly
subjected to
reverse phase preparative HPLC to isolate the title compound. MS found for
C24Hi7C1N603S (M+H)+ 505.1, 507.1 (Cl pattern).
EXAMPLE 138
5-Chloro-N-((1-(2-(2-methoxypyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (138)
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N O
CI
N-N H
N~,N
p I O
N
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25H19C1N603S (M+H)+ 519.1.
EXAMPLE 139
N-((1-(2-(2-Aminopyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (139)
N NH2
CI
N-N H
O
O
N
5 -Chloro-N-((1-(2-(2-fluoropyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (22 mg, 0.04 mmol) was
dissolved in
2.5 mL DMSO in a sealed tube. To it was added sodium azide (26 mg, 0.4 mmol)
and the
mixture was stirred overnight at 120 C. It was diluted with 100 mL chloroform
and
washed with brine twice. The organic phase was dried, concentrated in vacuo,
dissolved in
2 mL ethanol and 2 mL acetice acid. The mixture was treated with iron powder
(20 mg) at
100 C for 3 hrs, filtered and subjected to reverse phase preparative HPLC to
isolate the title
compound. MS found for C24H18C1N702S (M+H)+ 504.1, 506.1 (Cl pattern).
EXAMPLE 140
5-Chloro-N-((1-(2-(2-(dimethylamino)pyridin-4-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (140)
130
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L
N C CI
N-N H S ~
O Nv N \
O
I N
-Chloro-N-((1-(2-(2-fluoropyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (22 mg, 0.04 mmol) was
dissolved in 3
mL DMSO in a sealed tube. To it was added dimethylamine (2 M in THF, 0.2 mL,
0.4
5 mmol) and the mixture was stirred overnight at 120 C. It was concentrated
and directly
subjected to reverse phase preparative HPLC to isolate the title compound. MS
found for
C26H22C1N702S (M+H)+ 532.1, 534.1 (Cl pattern).
EXAMPLE 141
5-Chloro-N-((1-(2-(2-(methylamino)pyridin-4-yl)-4-(2-oxopyridin- l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (141)
H
N N
CI
N-N H
O Nv ,N
N O
The title compound was prepared using a similar procedure as described in
Example
140. MS found for C25H20C1N702S (M+H)+ 518.1, 520.1 (Cl pattern).
EXAMPLE 142
5-Chloro-N-((1-(2-(6-hydroxypyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (142)
OH
N CI
N-N H
O **-z Nv ,N
O
N
131
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The title compound was prepared using a similar procedure as described in
Example
137 from 5-chloro-N-((1-(2-(6-fluoropyridin-3-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (prepared as shown in
Example 136).
MS found for C24H17C1N603S (M+H)+ 505.1, 507.1 (Cl pattern).
EXAMPLE 143
5-Chloro-N-((1-(2-(6-methoxypyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (143)
O/
N CI
N-N H S
O \ N14r)~ N
O
I N
The title compound was prepared using a similar procedure as described in
Example
125. MS found for C25H19C1N603S (M+H)+ 519.1.
EXAMPLE 144
N-((1-(2-(6-Aminopyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (144)
NH2
N CI
N-N H
O S ~
N~~N ~
O
N
The title compound was prepared using a similar procedure as described in
Example
139. MS found for C24HigC1N702S (M+H)+ 504.1, 506.1 (Cl pattern).
EXAMPLE 145
5-Chloro-N-((1-(2-(6-(dimethylamino)pyridin-3-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (145)
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N.01
N CI
N =N N
O S ~
~
IN O
The title compound was prepared using a similar procedure as described in
Example
140. MS found for C26H22C1N7O2S (M+H)+ 532.1, 534.1 (Cl pattern).
EXAMPLE 146
5-Chloro-N-((1-(2-(6-(methylamino)pyridin-3-yl)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (146)
NH
N CI
/
N-N H
O S ~
\ N~~N ~
N O
The title compound was prepared using a similar procedure as described in
Example
141. MS found for C25H20C1N702S (M+H)+ 518.1, 520.1 (Cl pattern).
EXAMPLE 147
N-((1-(2-(3 -Amino-3-oxopropylcarbamoyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (147)
H CI
H2NY****~ N O
N-N H S ~
0 0 N ~
O
N
The title compound was prepared using a similar procedure as described in
Example
101. MS found for C23H2OC1N704S (M+H)+ 526.1, 528.1 (Cl pattern).
133
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EXAMPLE 148
N-((1-(2-(2-(1 H-Imidazol-1-yl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (148)
No
CI
O N-N H S ~
N~N ~
O
N O
The title compound was prepared using a similar procedure as described in
Example
165 below. MS found for C24H2OC1N703S (M+H)+ 522.1, 524.1 (Cl pattern).
EXAMPLE 149
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(pyridin-4-yl)ethoxy)phenyl)-1
H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (149)
N~ I
CI
O N-N H
N~~
O N
NI\
/ O
The title compound was prepared using a similar procedure as described in
Example
165 below. MS found for C26H21C1N603S (M+H)+ 533.1, 535.1 (Cl pattern).
EXAMPLE 150
3-(2-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1 H-1,2,3-triazol-l -yl)-5-
(2-
oxopyridin-1(2H)-yl)phenoxy)propylmorpholine-4-carboxylate (150)
Oj~ CI
rN\O O N=N H S ~
OJ O NN ~
N I O
134
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The title compound was prepared using a similar procedure as described in
Example
165 below. MS found for C27H27C1N606S (M+H)+ 599.1, 601.1 (Cl pattern).
EXAMPLE 151
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-2-yloxy)phenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (151)
N CI
N-N H S ~
O ~N ~
N O
The title compound was prepared using using a similar procedure as described
in
Example 57. MS found for C24H17C1N603S (M+H)+ 505.1, 507.1 (Cl pattern).
EXAMPLE 152
2-(2-(4-((5-Chlorothiophene-2-carboxamido)methyl)-5-iodo-lH-1,2,3-triazol-l-
yl)-5-(2-
oxopyridin-1(2H)-yl)phenoxy)acetic acid (152)
O~O H
CI
O N=N H S ~
O N ~
I \ Y "
N
N / II O
The title compound was prepared by a similar procedure as described in the
above
Examples. MS found for C21H15C1IN505S (M+H)+ 612Ø
EXAMPLE 153
5-Chloro-N-((1-(2-(3-hydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-5-iodo-l
H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (153)
135
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OH
CI
O N=N H S
N~N ~
p
I ~
N / 1 O
The title compound was prepared by a procedure similar to that described in
the
above Examples. MS found for C23H21C1IN504S (M+H)+ 612Ø
EXAMPLE 154
5-Chloro-N-((1-(2-((R)-2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
5-iodo-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (154)
OH
OH
CI
O N=N N H S ~
O ~ N ~
/ I O
I
The title compound was prepared by a procedure similar to that described in
the
above Examples. MS found for C22H19C1IN505S (M+H)+ 628.1.
EXAMPLE 155
5-Chloro-N-((1-(2-((S)-2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
5-iodo-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (155)
OH
OH
CI
O N=N H S ~
O ~ N_ N ~
N / O
The title compound was prepared by a procedure similar to that described in
the
above Examples. MS found for C22H19C1IN505S (M+H)+ 628.1.
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EXAMPLE 156
N-((1-(2-(2-(1 H-Pyrazol-1-yl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (156)
N
N
CI
O N-N H S ~
NON ~
O I O
/
N
The title compound was prepared using a similar procedure as described in
Example
165 below. MS found for C24H2OC1N703S (M+H)+ 522.1, 524.1 (Cl pattern).
EXAMPLE 157
5-Chloro-N-((1-(4-(2-oxopiperidin-1-yl)-2-thiomorpholinophenyl)-1 H-1,2,3-
triazol-4-
yl)methyl)thiophene-2-carboxamide (157)
S) cl
N N-N H S
Nv`~N
O I O
/
N
The title compound was prepared using a similar procedure as described in
Example
1. MS found for C23H25C1N602S2 (M+H)+ 517.1, 519.1 (Cl pattern).
EXAMPLE 158
5-Chloro-N-((1-(4-(2-oxopiperidin-l-yl)-2-((1,1-dioxo)thiomorpholino)phenyl)-
l H-1,2,3 -
triazol-4-yl)methyl)thiophene-2-carboxamide (158)
O~~O
CI
N N-N H S
N
O I O
N
137
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The title compound was prepared from 5-chloro-N-((1-(4-(2-oxopiperidin-l-yl)-2-
thiomorpholinophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide
using a
similar procedure as described in Example 12. MS found for C23H25C1N604S2
(M+H)+
549.1, 551.1 (Cl pattern).
EXAMPLE 159
5-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopiperidin-1-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (159)
H
O~N
NJl N-N H CI
S ~
O I ~ Nv `~N \
N / O
The title compound was prepared using a similar procedure as described in
Example
1. MS found for C23H24C1N703S (M+H)+ 514.1, 516.1 (Cl pattern).
EXAMPLE 160
5-Chloro-N-((1-(2-(morpholinomethyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)thiophene-2-carboxamide (160)
O CI
N
N-N H
O Nv vN
O
N
The title compound was prepared using a similar procedure as described in
Example
121. MS found for C24H23C1N603S (M+H)+ 511.1, 513.1 (Cl pattern).
EXAMPLE 161
5-Chloro-N-((1-(2-((3-oxopiperazin-1-yl)methyl)-4-(2-oxopyridin- l (2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (161)
138
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HN") CI
O/N N- -N H
O Nv N
O
N
The title compound was prepared using a similar procedure as described in
Example
121. MS found for C24H22C1N703S (M+H)+ 524.1, 526.1 (Cl pattern).
EXAMPLE 162
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(thiomorpholinomethyl)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (162)
S CI
N
N-N H
O S
Nv N
N O
The title compound was prepared using a similar procedure as described in
Example
121. MS found for C24H23C1N602S2 (M+H)+ 527.1, 529.1 (Cl pattern).
EXAMPLE 163
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1,-
dioxothiomorpholinomethyl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (163)
0
O% CI
N
N-N H
O Nv N
O
N
The title compound was prepared from Example 162 using a similar procedure as
described in Example 12. MS found for C24H23C1N604S2 (M+H)+ 559.1, 561.1 (Cl
pattern).
139
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EXAMPLE 164
5-Chloro-N-((1-(2-ethoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-
yl)methyl)thiophene-2-carboxamide (164)
CI
N=N H
~N1
The title compound was prepared using a similar procedure as described in
Example
74. MS found for C21Hi8C1N5O3S (M+H)+ 456.1, 458.1 (Cl pattern).
EXAMPLE 165
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-3-ylmethoxy)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (165)
N
CI
O N-N H S ~
O NN ~
N O
SCHEME 13
CI CI
F N-N H S OH N-N H S~
O Nv vN O \ 4`0 _ N `
O1.6 13.1
N
CI
O N-N H S
NQ;~ N
O
-tr
O
13.2
140
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Step 1:
To a solution of compound 1.6 (6.43 g, 15 mmol) in 45 mL DMSO and 15 mL water
was added sodium hydroxide (1.80 g, 45 mmol). The mixture was stirred in a
sealed flask
at 140 C for 16 hrs. After it was cooled to RT, 100 mL 1N sulfuric acid and
200 mL water
were added carefully. The mixture was vigorously stirred and chilled in ice
bath. The solid
precipitate was collected using a Buchner funnel and rinsed with cold DI
water, and dried in
vacuo to give compound 13.1 (4.10 g, 64 %). MS found for C19H14C1N503S (M+H)+
428.1, 430.1 (Cl pattern).
Step 2:
Compound 13.1 (43 mg, 0.1 mmol) was dissolved in 2 mL DMSO. To it were
added sodium carbonate (64 mg, 0.6 mmol) and 2-
bromomethylpyridine.hydrogenbromide
(51 mg, 0.2 mmol). The mixture was stirred in 60 C bath for 30 min to afford
title
compound 13.2, which was isolated directly using prep HPLC as a white powder.
MS
found for C25H19C1N603S (M+H)+ 519.1, 521.1 (Cl pattern).
EXAMPLE 166
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(N-(pyridine-3-yl)pyridin-3-
ylmethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (166)
ci
O N-N H S ~
Nv N \
O I O
N
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C25H19C1N603S (M)+ 610.1.
EXAMPLE 167
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-4-ylmethoxy)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (167)
141
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N
CI
Y
O N S
p J(: N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C25H19C1N603S (M+H)+ 519.1, 521.1 (Cl pattern).
EXAMPLE 168
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(pyridin-2-yl)ethoxy)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (168)
N
CI
O N-N H
N
p
N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C26H21C1N603S (M+H)+ 533.1, 535.1 (Cl pattern).
EXAMPLE 169
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(pyridin-2-ylmethoxy)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (169)
I \
iN
CI
O N o
p N O
142
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The title compound was prepared using a similar procedure as described in
Example
165. MS found for C25H19C1N603S (M+H)+ 519.1, 521.1 (Cl pattern).
EXAMPLE 170
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(quinolin-2-ylmethoxy)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (170)
/I
iN
CI
O N-N H
O I ~ Nv N
/ O
N
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C29H21C1N603S (M+H)+ 569.1, 571.1 (Cl pattern).
EXAMPLE 171
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(thiazol-4-ylmethoxy)phenyl)-1H-
1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (171)
S--,\
N
CI
O N-N H S ~
O I ~ Nv N \
N / O
I
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C23H17C1N603S2 (M+H)+ 525.1, 527.1 (Cl pattern).
EXAMPLE 172
5-Chloro-N-((1-(2-((2-methylthiazol-4-yl)methoxy)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1 H-
1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (172)
143
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S4
N
CI
O nN~ N
p I
N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C24H19C1N603S2 (M+H)+ 539.1, 541.1 (Cl pattern).
EXAMPLE 173
N-((1-(2-((1H-Benzo[d]imidazol-2-yl)methoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-
1H-
1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (173)
p
N,N NH
CI
O nN~ N
p I
N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C27H20C1N703S (M+H)+ 558.1, 560.1 (Cl pattern).
EXAMPLE 174
5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(pyridin-3-yl)ethoxy)phenyl)-1
H-1,2,3-
triazol-4-yl)methyl)thiophene-2-carboxamide (174)
I
N
CI
O N-N H
O \ Nv vN
NI O
144
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The title compound was prepared using a similar procedure as described in
Example
165. MS found for C26H21C1N603S (M+H)+ 533.1, 535.1 (Cl pattern).
EXAMPLE 175
N-((1-(2-((1,2,4-Oxadiazol-3-yl)methoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-
triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (175)
O-%\
N N
Y CI
N=N O N b
O I N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C22H16C1N704S (M+H)+ 510.1, 512.1 (Cl pattern).
EXAMPLE 176
5-Chloro-N-((1-(2-((1-methyl-lH-imidazol-2-yl)methoxy)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (176)
f==\
N N~
Y CI
`O N N=N / N S ~
~
O
11
N 0
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C24H2OC1N703S (M+H)+ 522.1, 524.1 (Cl pattern).
EXAMPLE 177
N-((1-(2-((1 H-Imidazol-2-yl)methoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3-triazol-
4-yl)methyl)-5-chlorothiophene-2-carboxamide (177)
145
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NY ~ NH
CI
O N-N H
O ~ Nv vN \
N O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C23HigC1N703S (M+H)+ 508.1, 510.1 (Cl pattern).
EXAMPLE 178
N-((1-(2-((1-((1H-Imidazol-2-yl)methyl)-1H-imidazol-2-yl)methoxy)-4-(2-
oxopyridin-
1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide
(178)
N~ N
N
H CI
O N-N H N S ~
O I ~ Nv N \
/ O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C27H22C1N903S (M+H)+ 588.1.
EXAMPLE 179
5-Chloro-N-((1-(2-((5-methylisoxazol-3-yl)methoxy)-4-(2-oxopyridin-1(2H)-
yl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (179)
O
N
CI
O N-N H
O ~ Nv vN
I N O
/
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C24H19C1N604S (M+H)+ 523.1, 525.1 (Cl pattern).
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EXAMPLE 180
N-((1-(2-(2-(1 H-Pyrrol-l-yl)ethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1 H-
1,2,3 -triazol-4-
yl)methyl)-5-chlorothiophene-2-carboxamide (180)
C
CI
O N~N
O
NI \
/ O
The title compound was prepared using a similar procedure as described in
Example
165. MS found for C25H21C1N603S (M+H)+ 521.1, 523.1 (Cl pattern).
EXAMPLE 181
This example illustrates methods for evaluating the compounds of the
invention,
along with results obtained for such assays. The in vitro and in vivo human
Factor Xa
activities of the inventive compounds can be determined by various procedures
known in
the art, such as a test for their ability to inhibit the activity of human
plasma Factor Xa. The
potent affinities for human Factor Xa inhibition exhibited by the inventive
compounds can
be measured by an ICSo value (in nM). The IC50 value is the concentration (in
nM) of the
compound required to provide 50 % inhibition of human Factor Xa proteolytic
activity. The
smaller the IC50 value, the more active (potent) is a compound for inhibiting
Factor Xa
activity.
An in vitro assay for detecting and measuring inhibition activity against
Factor Xa is
as follows:
IC50 and Ki Determinations:
Substrate:
The substrate S-2765 (Z-D-Arg-Gly-Arg-pNA=HC1) was obtained from Diapharma
(West
Chester, OH).
Enzyme:
The human plasma protein factor Xa was purchased from Haematologic
Technologies
(Essex Junction, VT).
Methods:
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ICso determinations
All assays, which are performed in 96-well microtiter plates, measure
proteolytic
activity of the enzyme (factor Xa) by following cleavage of a paranitroanilide
peptide
substrate. The assay buffer used for proteolytic assays was Tris buffered
saline (20 mM
Tris, 150 mM NaC1, 5mM CaC12, 0.1 % Bovine serum albumin (BSA), 5 % Dimethly
Sulfoxide (DMSO) pH 7.4). In a 96-well microtiter plate, inhibitor was
serially diluted to
give a range of final concentrations from 0.01 nM to 10 M. Duplicate sets of
wells were
assayed and control wells without inhibitor were included. Enzyme was added to
each well,
(factor Xa concentration = 1 nM), the plate was shaken for 5 seconds and then
incubated for
5 minutes at room temperature. S-2765 was added (100 M final) and the plate
was shaken
for 5 seconds (final volume in each well was 200 1). The degree of substrate
hydrolysis
was measured at 405 nm on a Thermomax plate reader (Molecular Devices,
Sunnyvale, CA)
for 2 minutes. The initial velocities of substrate cleavage (mOD/min), for
each range of
inhibitor concentrations, were fitted to a four parameter equation using
Softmax data
analysis software. The parameter C, derived from the resulting curve-fit,
corresponded to
the concentration for half maximal inhibition (IC5o)=
Ki determination
The assay buffer for this series of assays was Hepes buffered saline (20 mM
Hepes,
150 mM NaC1, 5 mM CaC12, 0.1 % PEG-8000, pH 7.4). In a 96-well microtiter
plate,
inhibitor was serially diluted in a duplicate set of wells to give a range of
final
concentrations from 5 pM to 3 M. Controls without inhibitor (8 wells) were
included.
The enzyme, factor Xa (final concentration = 1 nM) was added to the wells. The
substrate
S-2765 (final concentration = 200 M) was added and the degree of substrate
hydrolysis
was measured at 405 nm on a Thermomax plate reader for 5 minutes, using
Softmax
software. Initial velocities (mOD/min) were analyzed by non-linear least
squares regression
in the Plate K; software (BioKin Ltd, Pullman, WA) [Kusmic, et al., Analytical
Biochemistry 281: 62-67, 2000]. The model used for fitting the inhibitor dose-
response
curves was the Morrison equation. An apparent Ki (Ki*) was determined. The
overall Ki
was calculated using the following equation:
Ki *
Ki = 1 + [S]
Km
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where [S] is substrate concentration (200 M) and Kõ, is the Michaelis
constant for S-2765.
The following compounds exhibited Factor Xa IC50 values of less than or equal
to
100 nM: 1-6, 10-18, 20-26, 28-30, 42-45, 50-54, 56, 57, 63, 64, 67, 68, 74-76,
78-80, 82,
83, 85, 86, 88-95, 98, 99, 101-103, 109, 114, 117, 119-121, 125, 126, 133-135,
137-146,
148, 150-152, and 155-180.
The following compounds exhibited Factor Xa IC50 values of greater than 100 nM
and less than 500 nM: 96, 100, 104-108, 110-113, 115, 116, 118, 147, 153, and
154.
Thus, as examples, the data show that a variety of compounds of Formulas (I),
(II),
(Ia) and (Ib) are highly active Factor Xa inhibitors.
The present invention provides a number of embodiments. It is apparent that
the
examples may be altered to provide other embodiments of this invention.
Therefore, it will
be appreciated that the scope of this invention is to be defined by the
appended claims rather
than by the specific embodiments, which have been represented by way of
example.
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